8-hydroxy-7-substituted quinolines as anti-viral agents

ABSTRACT

The present invention provides for 8-hydroxy-7-substituted quinoline compounds such as formula IA                    
     These compounds are useful as anti-viral agents. Specifically, these compounds have anti-viral activity against the herpes virus, cytomegalovirus (CMV). Many of these compounds are also active against other herpes viruses, such as the varicella zoster virus, the Epstein-Barr virus, the herpes simplex virus and the human herpes virus type 8 (HHV-8).

CROSS-REFERENCE TO RELATED APPLICATIONS

The present patent application is a divisional U.S. patent applicationSer. No. 08/924,683, filed Sep. 5, 1997, now pending, which claims thebenefit of U.S. Ser. No. 60/025,870, filed Sep. 10, 1996, and U.S. Ser.No. 60/050,720, filed Jun. 25, 1997.

FIELD OF THE INVENTION

The present invention provides for 8-hydroxy-7-substituted quinolinecompounds and pharmaceutically acceptable salts thereof which are usefulas antiviral agents. The invention also relates to a pharmaceuticalcomposition containing such compound in combination with a suitableexcipient, the composition being useful in combating viral infections.The invention also relates to a method for selectively combating viralinfections in animals, including man. Specifically, these compounds haveanti-viral activity against the herpes virus, cytomegalovirus (CMV).Many of these compounds are also active against other herpes viruses,such as the varicella zoster virus, the Epstein-Barr virus, the herpessimplex virus, and the human herpes virus type 8 (HHV-8).

BACKGROUND OF THE INVENTION

The herpesviruses comprise a large family of double stranded DNAviruses. The herpesvirus family can be divided into three subfamilies(α, β, γ) based upon a number of biological properties such as hostrange and tropism, viral life cycle, and viral persistence and latency.Eight of the herpesviruses, herpes simplex virus types 1 and 2 (HSV-1and HSV-2), varicella zoster virus (VZV), human cytomegalovirus (HCMV),Epstein-Barr virus (EBV), and human herpes viruses 6, 7, and 8 (HHV-6,HHV-7, and HHV-8), have been shown to infect humans.

HSV-1 and HSV-2 are the prototypic a-herpesviruses. These two serotypesshare approximately 50% nucleotide homology. Both are neurotropicviruses, but their primary sites of replication are (different. HSV-1typically infects the oral mucosa resulting in ulcerations commonlyrefered to as cold sores. HSV-2 infects and cuases ulcerations of thegenital mucosa. HSV infection can also result in disseminated diseaseand encephalitis, especially in immunocompromised patients. D. O. Whiteand F. J. Fenner, In Medical Virology, D. O. White and F. J. Fenner,eds., Academic Press, p. 318-347 (1994).

VZV is also an α-herpesvirus and is the causitive agent of chicken pox.VZV establishes a latent infection in the dorsal root ganglia of theperipheral nervous system. From its latent site, VZV can cause recurrentdisease commonly refered to as shingles or zoster. The probability ofshingles increases with age and frequently occurs in immunocompromisedpatients. A. M. Arvin, In Virology, B. N. Field, D. M. Knipe, and P. M.Howley, ed., Lippincott-Raven Press, New York, p. 2547-2586 1996).

Human cytomegalovirus (HCMV), a β-herpesvirus, is an ubiquitous agentproducing infection in individuals of all age groups. Infection rates of60-100%, depending on geographic area and socioeconomic status have beenreported. R. J. Whitley, S. Goldsmith and J. Gnann, In Society forGeneral Microbiology. 45th Symposium: Control of Virus Diseases,Mimmock, N. J.; P. D. Griffiths and C. R. Madely, eds., CambridgeUniversity Press, Cambridge, p. 315 (1990). The majority of infectionsare asymptomatic. However infections occuring in the immuno-compromisedpatient, including organ transplant recipients and individuals with AIDSmay be severe and include HCMV induced pneumonia, colitis, andretinitis. L. W. Drew, Clin. Infect. Dis. 14:608-615 (1992). HCMV is theleading cause of blindness in AIDS patients. T. C. Merigan and S. Resta,Rev. Infect. Dis.12:S693 (1990). HCMV also establishes lifelong latencyin the host.

HCMV DNA polymerase (HCMV pol) is an enzyme essential for viralreplication. D. H. Spector, K. M. Klucher, D. K. Rabert and D. A.Wright, In Herpesvirus Transcription and Its Regulation, E. K. Wagner,ed., CRC Press, Boca Raton, Fla., p. 261 (1991). The current therapiesfor HCMV; Ganciclovir, Foscarnet and Vistide act by inhibition of HCMVpol. A. K. Field and K. K. Biron, Clin. Micro. Reviews 7:(1) 1-13(1994). See also U.S. Pat. Nos. 4,199,574; 4,215,113; 4,355,032; and E.DeClercq et al., Antiviral Research, Vol 8, pages 261-272 (1987).Ganciclovir and Foscarnet display significant toxicity and inductiontherapy is restricted to an intravenous route of administration. D.Faulds and R. C. Heel, Drugs, 39:597 (1990). Maintenance therapy withGanciclovir and Foscarnet will likely contribute to drug resistantvirus. A. K. Field and K. K. Biron, Clin. Micro. Reviews 7:(1) 1-13(1994). Clearly less toxic, orally bioavailable alternatives are needed.

EBV is a γ-herpesvirus which replicates in the epithelial cells of thenasopharynx and salivary glands and resides latently in B-cells.Childhood infections of EBV are normally asymptomatic. However, EBVinfection is associated with several diseases in adults such asinfectious mononucleosis, Burkitt's lymphoma, nasopharyngeal carcinoma,and Hodgkins disease. A. B. Rickinson and E. Kieff, In Virology, B. N.Fields, D. M. Knipe, and P. M. Howley, eds., Lippincott-Raven Press, NewYork, p. 2397-2446 (1996).

HHV-6 is a β-herpesvirus which causes roseola (exanthem subitum) inchildren. P. Lusso, Antivir. Res. 31:1-21 (1996). HHV-7 shares 50-60%nucleotide sequence homology with HHV-6. It's disease association isunclear, but it may be involved in some cases of roseola. N. Frenkel andE. Roffman, In Virology, B. N. Fields, D. M. Knipe, P. M. Howley, eds.,Lippincott-Raven Press, New York, p. 2609-2622 (1996). HHV-8, also knownas Kaposi's sarcoma associated herpesvirus (KSHV), is a γ-herpesviruswhich has recently been associated with Kaposi's sarcoma in AIDSpatients and multiple myeloma. M. B. Rettig et al., Science,276:1851-1854 (1997).

Information Disclosure

Published Japanese patent application H1-136152 published May 29, 1989discloses a silver halide photographic light-sensitive materialcomprising a support, and thereon, at least 1 silver halide emulsionlayer containing a cyan dye-forming coupler represented by a broadgeneric formula. This broad generic formula includes 8-hydroxy-quinolinederivatives substituted by a wide variety of substituents, e.g.,substituted carboxamide groups at the 7-position. None of the specificcompounds disclosed in this reference are structurally similar to thecompounds of the present invention. Also, the compounds of the presentinvention are useful as pharmaceutical agents, specifically HCMVinhibitors, whereas the reference compounds are useful in colorphotography.

Published Japanese patent application HEI 3-73949 published March 28,1991 discloses a thermally developable color light-sensitive materialcomprising at least a light-sensitive silver halide, a reducing agent, abinder, and a coupler represented by a first generic formula and/or asecond generic formula on a support. These broad generic formulasinclude 8-hydroxy-quinoline derivatives substituted by a wide variety ofsubstituents, e.g., substituted carboxamide groups at the 7-position. Asnoted for the previous Japanese reference, none of the specificcompounds disclosed in this reference are structurally similar to thecompounds of the present invention. Also, the compounds of the presentinvention are useful as pharmaceutical agents, specifically HCMVinhibitors, whereas the reference compounds are useful in colorphotography.

Published Japanese patent application 02152966 A2 discloses4-hydroxy-carbostyryl derivatives as anti-allergy and antiinflammatoryagents. The compounds of the present invention are1-N-unsubstituted)-8-hydroxy-7-quinolinecarboxamides.

U.S. Pat. No. 4,959,363 discloses1-(N-substituted)-1,4-dihydro-4-oxo-6-and/or-7-substituted-3-quinolinecarboxamidesas antiviral agents. The compounds of the present invention are1-(N-unsubstituted)-8-hydroxy-7-quinolinecarboxamides.

U.S. Pat. Nos. 5,459,146 and 5,506,236 disclose4-substituted-3-alkyl-pyrazolo[3,4-b]quinoline compounds as antiviralagents. Basically, these compounds are the tricyclic version ofcompounds such as those disclosed in the '363 patent above, and arestructurally very different from the compounds of the present invention.

U.S. Pat. No. 5,378,694 discloses compounds such as1-(N-substituted)-3-substituted-4-hydroxy-2-quinolinones, andgenerically, 3-substituted-4-hydroxycoumarin compounds as antiviralagents. U.S. Pat. No. 5,412,104 discloses compounds similar to thosedisclosed in the '694 patent for anti-viral or anti-hypertensive use;however, these 1-(N-substituted) reference compounds are disclosed ashaving substituents other than hydroxy at the 4-position of thequinolinone ring. The compounds of the present invention are1-(N-unsubstituted)-8-hydroxy-7-quinolinecarboxamides.

German patent DE 1 908 548 discloses a variety of compounds including4-hydroxy-quinoline compounds which may be substituted at the 3-positionby carboxamide groups, and which are useful against cold viruses.

Published German patent application DE 44 25 647 A1 disclosesheterocyclic-1-phenyl substituted quinolone and naphthyridone carboxylicacids for treating retroviral infections; Published German patentapplication DE 44 25 648 A1 discloses 6 and 6,8-substituted1-[4-(1H-1,2,4-triazol-1-yl-methyl)phenyl]quinolone carboxylic acids fortreating retroviral infections; Published German patent application DE44 25 650 A1 discloses substituted triazolylmethylphenyl-naphthyridonecarboxylic acids for treating retroviral infections; Published Germanpatent application DE 44 25 659 A1 discloses N1-diverse6-fluoro-8-difluoromethoxy substituted quinolone carboxylic acids fortreating retroviral infections. The compounds of these references arestructurally very different from the compounds of the present invention.

Derwent Abstract 96-246942/25 of JP 8099957-A discloses optionallyheterocyclyl substituted 4-oxo-quinoline and naphthyridine derivativeswhich are useful for treating herpes, particularly herpes simplex virus,herpex zoster virus and cytomegalovirus.

Derwent Abstract 95-271358/36 of JP 7165748-A discloses compounds havingheterocyclic ketones which are used in antiviral agents for treatingcytomegalovirus infectious disease.

Nowhere do these references teach or suggest the specific8-hydroxyquinoline-7-carboxamide compounds of the present inventionwhich are useful as anti-HCMV agents.

U.S. Pat. No. 5,463,072 discloses a process for the preparation ofnaphtholic 2-equivalent cyan couplers which are useful in colorphotography. It discloses an 8-hydroxy-quinoline compound having asubstituted triazole moiety at the 6-position and a carbamoyl moiety atthe 7-position.

International Publication WO 95/11592, published May 4, 1995, disclosesa marine structure carrying a coating comprising a layer which containsa quinoline compound, or an N-oxide or a salt thereof, havingantifouling activity. It generically discloses such compounds with avariety of substituents, such as hydroxy, (optionally substitutedC₁₋₁₂-alkyl)sulphonyl, (optionally substituted aryl)sulphonyl, mono ordi (optionally substituted C₁₋₁₂alkyl)aminosulphonyl.

Derwent Abstract 91-232424/32 (Sandoz AG) discloses the use of 5HT-3antagonists for the prevention or reduction of dependence on alcohol,psycho-stimulants, nicotine or opiates. A variety of compounds isdisclosed including quinoline compounds having unsubstituted phenylrings.

Derwent Abstract 90-343755/46 (Sandoz Ltd.) discloses serotonin 5-HT3antagonists used for treating stress-related psychiatric disorders,rhinitis, nasal disorders and lung embolism. It discloses a variety ofcompounds, including quinoline compounds substituted by bridgedpiperidine groups.

Derwent Abstract 90-290145/38 (DuPont DeNemours Co.) disclosesn-substituted naphthalene or quinoline sulphonamides which are radio andchemo-sensitising agents in tumour treatment. Other than the sulfonamidebonds, the quinoline compounds are not further substituted on theirphenyl rings.

Derwent Abstract 90-264471/35 (Yoshitomi Pharm. Ind. KK.) discloses(iso)quinoline-sulphonamide compounds and their acid addition salts asvasodilators and cerebral circulation improving agents.

Derwent Abstract 85-063337/11 (Sandoz-Patent-Gmbh) discloses a varietyof new fused heterocyclic sulphonic amide and ester derivatives withanalgesic, antiarrythmic and antipsychotic activities.

Derwent Abstract 22,706 (Pfizer & Co.) discloses quinoline derivativesand their acid addition salts as bronchodilators, but no sulfonamidesubstituents are disclosed for these compounds.

U.S. Pat. No. 5,240,940 discloses fungicidal compositions comprising acombination of two fungicides, one of which is a quinoline or cinnolinecompound. U.S. Pat. No. 4,881,969 discloses sulfonamides as herbicidalagents.

European Published applications 0326330 and 0326328 discloses quinoline,quinazoline and cinnoline fungicides.

JP 63307451 discloses a silver halide color photographic photosensitivematerial with improved granularity containing a water-soluble couplercapable of a coupling reaction with an oxidant main ingredient in colordeveloping, which coupler may include specific 8-hydroxy-quinolinecompounds.

JPO7033729-A discloses the production ofN-cyano-N-substituted-arylcarboxyimidamide compounds in which aryl maybe 8-quinolyl groups.

International Publication Number WO 96/25399, published Aug. 22, 1996,discloses aroylaniline derivatives which exhibit anti-retroviralactivity.

International Publication Number WO 97/03069, published Jan. 30, 1997,discloses substituted heteroaromatic compounds which are proteintyrosine kinase inhibitors, in particular to substituted quinolines andquinazolines.

International Publication Number WO 96/06084, published Feb. 29, 1996,discloses quinolylamine derivatives which are useful for the treatmentof arrhythmia.

European Patent Application No. 0206751, published Dec. 30, 1996,discloses 2-substituted-phenylalkenyl-quinoline derivatives which areuseful as selective antagonists of leukotrienes of D₄.

International Application No. WO 9632015 discloses synergisticfungicidal compositions made of quinoline derivatives and cytochromecomplex III inhibitors.

European Patent Application No. 0399818 discloses diarylstyrylquinolinediacids which are leukotriene antagonists and inhibitors of leukotrienebiosynthesis. These compounds are useful as anti-asthmatic,anti-allergic, anti-inflammatory and cytoprotective agents.

SUMMARY OF THE INVENTION

The present invention particularly provides:

A compound of formula IA

wherein R⁰ is

a) —(CH₂)_(n)—X¹,

b) —(CH₂)_(n)—C₃-C₈ cycloalkyl substituted by zero (0) or one (1) R⁸,

c) —(CH₂)_(p)W¹X²,

d) —(CH₂)_(p)W¹CH₂X¹, or

e) —(CH₂)_(n)—CHR⁹—(CH₂)_(n)—X¹;

wherein R¹ is

a) —H,

b) —F,

c) —Cl,

d) —Br,

e) —CF₃, or

f) —NO₂;

wherein R² is

a) —H,

b) —C₁-C₃alkyl,

c) —OH,

d) —CF₃,

e) —CH═CH-furanyl,

f) —CH═CH-phenyl substituted by zero (0) or one (1) R⁴,

g) —CH═CH-pyridinyl,

h) —(CH₂)_(p)-phenyl substituted by zero (0) or one (1) R⁴,

i) —NHV¹,

j) —CH₂NHV¹, or

k) —CH₂Z¹;

wherein R³ is

a) —H,

b) —OH,

c) —CF₃, or

d) —C₁-C₃alkyl;

wherein R⁴ is

a) —H

b) —F,

c) —Cl,

d) —Br,

e) —NO₂,

f) —CF₃,

g) —W¹-R¹⁰,

h) —C₁-C₆ alkyl,

i) —C₃-C₈ cycloalkyl,

j) —[CH₂]_(n)-aryl,

k) —[CH₂]_(n)-het,

l) —CH₂—C₃-C₈ cycloalkyl,

m) —SO₂NH-het

n) —CN,

o) —I, or

p) —CH₂—OH;

wherein R⁵ is

a) —H,

b) —F,

c) —Cl,

d) —Br,

e) —W¹—R¹⁰,

f) —CF₃,

g) —C₁-C₆ alkyl,

h) —C₃-C₈ cycloalkyl,

i) —(CH₂)_(n)-aryl substituted by R^(6,)

j) —(CH₂)_(n)-het substituted by R^(7,) or

k) —CH₂—C₃-C₈ cycloalkyl;

wherein R⁶ is

a) —H,

b) —F,

c) —Cl, or

d) —Br;

wherein R⁷ is

a) —H,

b) —F,

c) —Cl, or

d) —Br;

wherein R⁸ is

a) —C₁-C₄ alkyl,

b) —W¹—H, or

c) —CH₂—W¹H;

wherein R⁹ is

a) —C₁-C₇ alkyl,

b) —C₃-C₈ cycloalkyl,

c) —C(O)R¹¹,

d) —C(O)NHR¹¹,

e) —CH(OH)R¹¹,

f) —CH₂OH,

g) —CO₂R¹¹, or

h) —aryl;

wherein R¹⁰ is

a) —H,

b) —C₁-C₆ alkyl,

c) —C₃-C₈ cycloalkyl,

d) —(CH₂)_(n)-aryl optionally substituted with F, Cl, CH₂OH or —NO₂,

e) —(CH₂)_(n)-het, or

f) —CH₂—C₃-C₈ cycloalkyl;

wherein R¹¹ is

a) —C₁-C₇ alkyl,

b) —C₃-C₈ cycloalkyl,

c) —(CH₂)_(n)X¹, or

d) —CH₂—C₃-C₈ cycloalkyl;

wherein X¹is

a) -aryl substituted by zero (0), one (1), two (2), or three (3) R⁴,

b) -het substituted by zero (0), one (1) or two (2) R⁵,

c) —C₁-C₈ alkyl,

d) —CH(OH)-phenyl,

e) —S-phenyl,

i) —NHSO₂-phenyl substituted by one (1), two (2) or three (3) R⁴,

g) —CN,

h) —OH,

i) —C₃-C₈ cycloalkyl substituted by zero (0), one (1) or two (2) R⁸, or

j) —4-cyano-2,3,5,6-tetrafluoro-phenyl;

wherein X² is

a) -aryl substituted by zero (0), one (1), two (2) or three (3) R⁴,

b) -het substituted by zero (0), one (1) or two (2) R⁵,

c) —C₁-C₈ alkyl,

d) —CH(OH)-phenyl, or

e) —C₃-C₈ cycloalkyl substituted by zero (0), one (1) or two (2) R⁸;

wherein W¹ is

a) —NH,

b) -oxygen, or

c) -sulfur;

wherein V¹ is

a) —R¹¹,

b) —C(O)R¹¹,

c) —SO₂R¹¹, or

d) —C(O)NH^(R) ¹¹;

wherein Z¹ is

a) —C₁-C₇ alkyl,

b) —C₃-C₈ cycloalkyl,

c) —C(O)R¹¹,

d) —C(O)NHR¹¹, or

e) —CO₂R¹¹;

wherein -aryl is

a) -phenyl,

b) -naphthyl,

c) -biphenyl,

d) -tetrahydro-naphthyl, or

e) fluorenyl;

wherein -het is a 5-, 6- or 7-membered saturated or unsaturated ringcontaining from one (1) to three (3) heteroatoms selected from the groupconsisting of nitrogen, oxygen and sulfur; and including any bicyclicgroup in which any of the above heterocyclic rings is fused to a benzenering or another heterocyclic;

wherein -cycloalkyl is a saturated or unsaturated hydrocarbon ringincluding any bicyclic group in which the above ring is connected to abenzene, heterocyclic or other hydrocarbon ring;

wherein n is zero (0) to six (6), inclusive;

wherein p is one (1), two (2) or three (3);

or a pharmaceutically acceptable salt or N-oxide thereof.

The present invention further provides:

The compound of formula IA provided that:

a) when R⁰ is —(CH₂)_(n)—X¹ and X¹ is —OH, then n is one or greater; and

b) when R⁰ is —(CH₂)_(p)W¹X², W¹ is -oxygen or -sulfur and X² is phenylthen

R⁴ is other than t-pentyl.

The present invention also provides:

A compound of formula I

wherein R¹ is

a) —H,

b) —F,

c) —Cl,

d) —Br,

e) —CF₃, or

f) —NO₂;

wherein R² is

a) —H,

b) —C₁-C₃alkyl,

c) —OH,

d) —CF₃,

e) —CH═CH-furanyl,

f) —CH═CH-phenyl substituted by zero (0) or one (1) R⁴,

g) —CH═CH-pyridinyl, or

h) —(CH₂)_(p)-phenyl substituted by zero (0) or one (1) R^(4;)

wherein R³ is

a) —H,

b) —OH,

c) —CF₃, or

d) —C₁-C₃alkyl;

wherein X¹ is

a) -phenyl substituted by zero (0) or one (1) R⁴,

b) -het substituted by zero (0) or one (1) R⁵,

c) —C₁-C₁₂alkyl,

d) —CH(OH)-phenyl,

e) —S-phenyl,

f) -naphthyl,

g) —NHSO₂-phenyl substituted by one (1) R⁴, or

h) —CN;

wherein het is

a) -1,3,4-thiadiazol-2-yl,

b) -4,5-dihydro-4-oxo-2-thiazolyl,

c) -thiazolyl,

d) -benzothiazolyl,

e) -pyridinyl,

f) -morpholinyl, or

g) -imidazolyl;

wherein R⁴ is

a) —H

b) —F,

c) —Cl,

d) —Br,

e) —NO₂,

f) —OCH₃,

g) —CF₃, or

h) —C₁-C₄ alkyl;

wherein R⁵ is

a) —H,

b) —F,

c) —Cl,

d) —Br,

e) —(CH₂)_(n)-(phenyl substituted by R⁶),

f) -thienyl substituted by R⁷, or

g) —OH;

wherein R⁶ is

a) —H,

b) —F,

c) —Cl, or

d) —Br;

wherein R⁷ is

a) —H,

b) —F,

c) —Cl, or

d) —Br;

wherein n is zero (0) to six (6) inclusive;

or a pharmaceutically acceptable salt or a N-oxide thereof.

The present invention further provides compounds of formula II

wherein R¹ is

a) —H,

b) —Cl,

c) —Br, or

d) —NO₂;

wherein R² is

a) —H,

b) —CH₃,

c) —CF₃,

d) —(CH₂)_(p)-phenyl substituted by zero (0) or one (1) R⁴,

e) —CH═CH-furanyl, or

f) —CH═CH-phenyl substituted by zero (0) or one (1) R⁴;

wherein X¹ is

a) -phenyl substituted by one (1) R⁴,

b) -het substituted by one (1) R⁵,

c) -CH(OH)-phenyl,

d) —S-phenyl,

e) -naphthyl,

i) —NHSO₂-phenyl substituted by one (1), two (2) or three (3) R⁴, or

g) —CN;

wherein het is

a) -1,3,4-thiadiazol-2-yl,

b) -4,5-dihydro-4-oxo-2-thiazolyl,

c) -2-thiazolyl, or

d) -2-benzothiazolyl;

wherein R⁴ is

a) —H,

b) —Cl,

c) —Br,

d) —NO₂, or

e) —OCH₃;

wherein R⁵ is

a) —H,

b) —Cl,

c) —(CH₂)_(n)-(phenyl substituted by R⁶),

d) -2-thienyl substituted by R⁷, or

e) OH;

wherein R⁶ is

a) —H,

b) —Cl, or

c) —Br;

wherein R⁷ is

a) —H,

b) —Cl, or

c) —Br.

In another aspect, the present invention provides

A use of a compound of formula IA to prepare a medicament for treating asusceptible cytomegaloviral infection in a mammal

wherein R⁰ is

a) —(CH₂)_(n)—X¹,

b) —(CH₂)_(n)—C₃-C₈ cycloalkyl substituted by zero (0) or one (1) R⁸,

c) —(CH₂)_(p)W¹X₂,

d) —(CH₂)_(p)W¹CH₂X¹,or

e) —(CH₂)_(n)—CHR⁹—(CH₂)_(n)—X¹;

wherein ¹ is

a) —H,

b) —F,

c) —Cl,

d) —Br,

e) —CF₃, or

f) —NO₂;

wherein R² is

a) —H,

b) —C₁-C₃alkyl,

c) —OH,

d) —CF₃,

e) —CH═CH-furanyl,

f) —CH═CH-phenyl substituted by zero (0) or one (1) R⁴,

g) —CH═CH-pyridinyl,

h) —(CH₂)_(p)-phenyl substituted by zero (0) or one (1) R⁴,

i) —NHV¹,

j) —CH₂NHV¹, or

k) —CH₂Z¹;

wherein R³ is

a) —H,

b) —OH,

c) —CF₃, or

d) —C₁-C₃alkyl;

wherein R⁴ is

a) —H

b) —F,

c) —Cl,

d) —Br,

e) —NO₂,

f) —CF₃,

g) —W¹—R¹⁰,

h) —C₁-C₆ alkyl,

i) —C₃-C₈ cycloalkyl,

j) —[CH₂]_(n)-aryl,

k) —[CH₂]_(n)-het,

l) —CH₂—C₃-C₈ cycloalkyl,

m) —SO₂NH-het

n) —CN,

o) —I, or

p) —CH₂—OH;

wherein R⁵ is

a) —H,

b) —F,

c) —Cl,

d) —Br,

e) —W¹—R¹⁰,

f) —CF₃,

g) —C₁-C₆ alkyl,

h) —C₃-C₈ cycloalkyl,

i) —(CH₂)_(n)-aryl substituted by R⁶,

j) —(CH₂)_(n)-het substituted by R⁷, or

k) —CH₂—C₃-C₈ cycloalkyl;

wherein R⁶ is

a) —H,

b) —F,

c) —Cl, or

d) —Br;

wherein R⁷ is

a) —H,

b) —F,

c) —Cl, or

d) —Br;

wherein R⁸ is

a) —C₁-C₄ alkyl,

b) —W¹—H, or

c) —CH₂W¹H;

wherein R⁹ is

a) —C₁-C₇ alkyl,

b) —C₃-C₈ cycloalkyl,

c) —C(O)R¹¹,

d) —C(O)NHR¹¹,

e) —CH(OH)R¹¹,

f) —CH₂OH,

g) —CO₂R¹¹, or

h) -aryl;

wherein R¹⁰ is

a) —H,

b) —C₁-C₆ alkyl,

c) —C₃-C₈ cycloalkyl,

d) —(CH₂)_(n)-aryl optionally substituted with F, Cl, CH₂OH or —NO₂,

e) —(CH₂)_(n)-het, or

f) —CH₂—C₃-C₈ cycloalkyl;

wherein R¹¹ is

a) —C₁-C₇ alkyl,

b) —C₃-C₈ cycloalkyl,

c) —(CH₂)_(n)X¹, or

d) —CH₂—C₃-C₈ cycloalkyl;

wherein X¹ is

a) -aryl substituted by zero (0), one (1), two (2), or three (3) R⁴,

b) -het substituted by zero (0), one (I) or two (2) R⁵,

c) —C₁-C₈ alkyl,

d) —CH(OH)-phenyl,

e) —S-phenyl,

f) —NHSO₂-phenyl substituted by one (1), two (2) or three (3) R⁴,

g) —CN,

h) —OH,

i) —C₃-C₈ cycloalkyl substituted by zero (0), one (1) or two (2) R⁸, or

j) -4-cyano-2,3,5,6-tetrafluoro-phenyl;

wherein X² is

a) -aryl substituted by zero (0), one (1), two (2) or three (3) R⁴,

b) -het substituted by zero (0), one (1) or two (2) R⁵,

c) —C₁-C₈ alkyl,

d) —CH(OH)-phenyl, or

e) —C₃-C₈ cycloalkyl substituted by zero (0), one (1) or two (2) R⁸;

wherein W¹ is

a) —NH,

b) -oxygen, or

c) -sulfur;

wherein V¹ is

a) —R¹¹,

b) —C(O)R¹¹,

c) —SO₂R¹¹, or

d) —C(O)NHR¹¹;

wherein Z¹ is

a) —C₁-C₇ alkyl,

b) —C₃-C₈ cycloalkyl,

c) —C(O)R¹¹,

d) —C(O)NHR¹¹, or

e) —CO₂R¹¹;

wherein -aryl is

a) -phenyl,

b) -naphthyl,

c) -biphenyl,

d) -tetrahydro-naphthyl, or

e) fluorenyl;

wherein -het is a 5-, 6- or 7-membered saturated or unsaturated ringcontaining from one (1) to three (3) heteroatoms selected from the groupconsisting of nitrogen, oxygen and sulfur; and including any bicyclicgroup in which any of the above heterocyclic rings is fused to a benzenering or another heterocyclic;

wherein -cycloalkyl is a saturated or unsaturated hydrocarbon ringincluding any bicyclic group in which the above ring is connected to abenzene, heterocyclic or other hydrocarbon ring;

wherein n is zero (0) to six (6), inclusive;

wherein p is one (1), two (2) or three (3);

or a pharmaceutically acceptable salt or N-oxide thereof; as well as amethod of treating a cytomegalovirus comprising the administration of aneffective amount of a compound of the formula IA.

The present invention also provides:

An antiviral pharmaceutical composition which comprises apharmaceutically acceptable excipient and an effective amount of acompound of formula I.

Further, the present invention provides:

A compound of the formula III

wherein R¹ is

a) —H,

b) —C₁-C₅ alkyl, or

c) —CH═CH-aryl;

wherein R² is

a) —C₁-C₁₀ alkyl,

b) —(CH₂)_(n)R³,

c) —CH(R⁴)R³, or

d) —(CH₂)_(n)—X²—R³;

wherein R³ is

a) -aryl,

b) -het substituted by zero (0) to two (2) R⁵, or

c) —C₃-C₆ cycloalkyl;

wherein R⁴ is

a) —C₁-C₅ alkyl, or

b) -aryl;

wherein X¹ is

a) —H,

b) —F,

c) —Cl,

d) —Br, or

e) —I;

wherein X² is

a) —O—,

b) —S—, or

c) —NH—;

wherein n is zero (0) to four (4) inclusive;

wherein aryl is

a) phenyl substituted by zero (0) to two (2) R⁵, or

b) naphthyl substituted by zero (0) to two (2) R⁵;

wherein het is a 5-, 6- or 7-membered saturated or unsaturated ringcontaining from one (1) to three (3) heteroatoms selected from the groupconsisting of nitrogen, oxygen and sulfur; and including any bicyclicgroup in which any of the above heterocyclic rings is fused to a benzenering or another heterocycle; and the ring may be connected through acarbon or secondary nitrogen in the ring or an exocyclic nitrogen; andif chemically feasible, the nitrogen and sulfur atoms may be in theoxidized forms; and if chemically feasible, the nitrogen atom may be inthe protected form;

wherein R⁵ is

a) —H,

b) —C₁-C₅ alkyl,

c) —F,

d) —Cl,

e) —OCH₃,

f) —CF₃,

g) —NHSO₂-het substituted by zero (0) to two (2) —C₁-C₅ alkyl, or

h) —NHSO₂-phenyl;

or a pharmaceutically acceptable salt thereof;

A compound of formula III

wherein R₁ is

a) —H,

b) —CH₃, or

c) —CH═CH-phenyl;

wherein R² is

a) —(CH₂)_(n)R³,

b) —(CH₂)_(n)—X²—R³, or

c) —CH(R⁴)R³;

wherein R³ is

a) -phenyl substituted by zero (0) to two (2) R⁶,

b) -het,

c) -naphthyl, or

d) —C₃₋₆ cycloalkyl;

wherein R⁴ is

a) —CH₃, or

b) -phenyl;

wherein R⁵ is

a) —F,

b) —Cl,

c) —NHSO₂-phenyl;

wherein X¹ is

a) —Cl, or

b) —Br;

wherein X¹ is

a) —O—, or

b) —S—;

wherein het is

a) -imidazolyl, or

b) -indolyl.

The present invention also provides:

A compound of the formula IV

where X¹ is

a) —H,

b) —F,

c) —Cl,

d) —Br, or

e) —I;

wherein R₂, R₃ and R₄ may be the same or different and are

a) —C₁-C₅ alkyl, or

b) -phenyl.

Also provided is:

A compound of formula V

wherein X¹ is

a) phenyl substituted by zero (0) to three (3) R⁴,

b) naphthyl substituted by zero (0) to three (3) R⁴,

c) fluorenyl substituted by zero (0) to three (3) R⁴,

d) het substituted by zero (0) to one (1) R⁵, or

e) 4-cyano-2,3,5,6-tetrafluorophenyl;

wherein R⁴ is

a) —F,

b) —Cl,

c) —Br,

d) —I,

e) —NO₂,

f) —CN,

g) —CF₃,

h) —C₁-C₆ alkyl,

i) phenyl,

j) cyclohexyl,

k) hydroxymethyl,

l) —OR¹⁰,

m) —SR¹⁰, or

n) —SO₂NH-het;

wherein het is

a) 1,3-benzodioxol-4-yl,

b) 1,3-benzodioxo-5-yl,

c) coumarinyl,

d) indazoyl,

e) indolyl,

f) benzothiazolyl,

g) benzothiadiazolyl,

h) quinolinyl,

i) pyridinyl,

j) 1,3,4-thiadiazol-2-yl, or

k) isoxazolyl substituted with one or two C₁-C₄ alkyl;

wherein R⁵ is

a) —F,

b) —Cl,

c) —Br,

d) —I,

e) —CF₃,

f) —C₁-C₄-alkyl, or

g) —C₁-C₂-alkylsubstituted with an aryl;

wherein R¹⁰ is

a) hydrogen,

b) —C₁-C₄ alkyl,

c) phenyl,

d) benzyl, or

e) 4-nitrophenyl; as well as

A compound of formula V

wherein het is

a) indazoyl,

b) indoyl, or

c) isoxazolyl substituted with one (1) or two (2) C₁-C₄ alkyl.

Finally, the present invention provides:

A compound of formula VI or VII

wherein X is

a) —C, or

b) —SO;

wherein Y is

a) —NH,

b) —O, or

c) —S;

wherein EWG is an electron withdrawing group;

wherein R¹, R² and R³ are as defined in claim 1;

wherein R⁴ is

a) —H,

b) —(CH₂)_(n)—CO₂—C₁-C₆ alkyl,

c) —(CH2)_(m)-phenyl optionally substituted with one (1) or two (2) R⁷,

d) —(CH₂)_(m)-het,

e) —C₁-C₆ alkyl optionally substituted by one R⁶,

f) —C₁-C₄ alkyl—NH—COOCH₂-benzyl, or

g) —C₁-C₄ alkyl—S—CH₁₃;

wherein R⁵ is pyrrolidin-1-yl optionally substituted with EWG or R^(6;)

wherein n is zero (0) to three (3);

wherein m is zero (0) to one (1);

wherein -het is a 5-, 6- or 7-membered saturated or unsaturated ringcontaining from one (1) to three (3) heteroatoms selected from the groupconsisting of nitrogen, oxygen and sulfur; and including any bicyclicgroup in which any of the above heterocyclic rings is fused to a benzenering or another heterocyclic;

wherein R⁶ is

a) hydroxy,

b) —C₁-C₆ alkyloxy,

c) mercapto, or

d) —C₁-C₆ alkylmercapto;

wherein R⁷ is

a) hydroxy, or

b) —C₁-C₆ alkyloxy; as well as

A compound of formula VI or VII

wherein R⁷ is t-butyl;

wherein EWG is

a) —NH—CO₂C(CH₃)₃,

b) —CN,

c) —COX²—C₁-C₆ alkyl, or

d) —COOH;

wherein X² is

a) —O—, or

b) —NH; and

wherein het is

a) 1,3-benzodioxol-4-yl,

b) 1,3-benzodioxol-5-yl, or

c) indolyl.

“Pharmaceutically acceptable salts” refers to those salts which possessthe biological effectiveness and properties of the parent compound andwhich are not biologically or otherwise undesirable.

“N-oxide” refers to the oxidized form of the nitrogen in the ring of the8-hydroxy-quinoline compounds of the present invention. The preparationof such compounds is well known to one of ordinary skill in organicchemistry, including methods such as oxidation withmetachloro-peroxy-benzoic acid.

“Electron-withdrawing group” means any substituent on the ring whichtends to draw electron density from the ring. Examples of such groupsinclude halogen, nitro, cyano, carboxylic acids, carboxylic esters,sulfoxides, sulfones, sulfonamides, ketones and aldehydes.

“Halogen” means fluroine, chlorine, or bromine.

“Het” is a 5-, 6- or 7-membered saturated or unsaturated ring containingfrom one (1) to three (3) heteroatoms selected from the group consistingof nitrogen, oxygen and sulfur; and including any bicyclic group inwhich any of the above heterocyclic rings is fused to a benzene ring oranother heterocycle; and the ring may be connected through a carbon orsecondary nitrogen in the ring or an exocyclic nitrogen; and ifchemically feasible, the nitrogen and sulfur atoms may be in theoxidized forms; and if chemically feasible, the nitrogen atom may be inthe protected form; and substituted or unsubstituted. Examples of “het”include the following: thiadiazolyl, thiazolyl, benzothiazolyl,pyridinyl (or pyridyl), morpholinyl, imidazolyl, indolyl, andpiperazinyl.

The compounds of the present invention are named according to the IUPACor CAS nomenclature system.

The carbon atom content of various hydrocarbon-containing moieties isindicated by a prefix designating the minimum and maximum number ofcarbon atoms in the moiety, i.e., the prefix C_(i)-C_(j) indicates amoiety of the integer “i” to the integer “j” carbon atoms, inclusive.Thus, for example, (C₁-C₃)alkyl refers to alkyl of one to three carbonatoms, inclusive, or methyl, ethyl, propyl and isopropyl, straight andbranched forms thereof.

Throughout this application, abbreviations which are well known to oneof ordinary skill in the art may be used, such as “Ph” for phenyl, “Me”for methyl, and “Et” for ethyl.

The following Charts A-I describe the preparation of the compounds ofthe present invention. All of the starting materials are prepared byprocedures described in these charts or by procedures analogous thereto,which would be well known to one of ordinary skill in organic chemistry.All of the final compounds of the present invention are prepared byprocedures described in these charts or by procedures analogous thereto,which would be well known to one of ordinary skill in organic chemistry.All of the variables used in the charts are as defined below or as inthe claims.

Chart A

The preparation of the starting materials,8-hydroxyquinoline-7-carboxylic acids, is accomplished in low tomoderate yields by the carboxylation of 8-hydroxy-quinolines, which areeither commercially available or which are prepared by literaturemethods: G. S. Bajwa, K. E. Hartman, and M. N. Jouillie, Journal ofMedicinal Chemistry, Vol.16, No. 2, pages 134-138 (1973); L. C. March,W. A. Romanchick, G. S. Bajwa, and M. M. Jouillie, Journal of MedicinalChemistry, Vol. 16, No. 4, pages 337-342 (1973). The compound of formulaA-1 is reacted with K₂CO₃ (3 eq.), CO₂(800 p.s.i) at 170° for 7 days, toyield the compound of formula A-2. J. Hannah et al., Journal ofMedicinal Chemistry, Vol. 21, No. 11, pages 1093-1100 (1978). (R¹ and R²in formula A-1 are the same as R¹ and R² in formula A-2.) The compoundof formula A-2 wherein R¹ is —H and R² is —H is the intermediatecompound of Preparation 1 below. The compound of formula A-2 wherein R¹is —F and R² is —H is the intermediate compound of Preparation 4 below.The compound of formula A-2 wherein R¹ is —Cl and R² is —H is theintermediate compound of Preparation 3 below. The compound of formulaA-2 wherein R¹ is —H and R2 is —CH₃ is the intermediate compound ofPreparation 5 below.

Chart B

Bromination of 8-hydroxyquinoline-7-carboxylic acid of formula B-1 withone equivalent of bromine (HOAc, reflux, 1 hr) yields5-bromo-8-hydroxy-7-quinoline-carboxylic acid of formula B-2 inquantitative yield, which is prepared in Preparation 2 below. R. Schmittand F. Engelmann, Chem. Ber., 20; 1887; 2694.

Chart C

The acid of formula C-1, prepared as described in Charts A and B above,is condensed with the amine of formula C-2, which is commerciallyavailable (e.g, p-chloro or p-nitrobenzylamine), under appropriateconditions (EDC is used as the coupling agent, HOBt, DMF, rt, 18 hr) toyield the compound of formula C-3. (R¹ and R² in formula C-1 are thesame as R¹ and R² in formula C-3. X in formula C-2 is the same as X informula C-3.) The compound of formula C-3 wherein R¹ is —Br, R2 is —Hand X is —Cl is the final compound of Example 9 below. The compound offormula C-3 wherein R¹ is —H, R² is —CH₃ and X is —Cl is the finalcompound of Example 10 below. The compound of formula C-3 wherein R¹ is—Cl, R² is —H and X is —Cl is the final compound of Example 11 below.The compound of formula C-3 wherein R¹ is —H, R² is —H and X is —NO₂ isthe final compound of Example 12 below. The compound of formula C-3wherein R¹ is —F, R² is —H and X is —Cl is the final compound of Example16 below. Chart C is the preferred coupling method for benzylamines.

Chart D

Under the same conditions as in Chart C above (i.e., EDC, HOBt, DMF, rt,7 days), the acid of formula D-1 is condensed with the heterocyclicamine of formula D-2 to give the final compound of formula D-3, which isprepared in Example 8 below.

Chart E

Chart E discloses a more efficient method of coupling the8-hydroxyquinoline-7-carboxylic acids with anilines and heterocyclicamines utilizing PCl₃ as the condensing agent. H. Singh, A. K. Singh, S.Sharma, R. N. Iyer, J. Med. Chem., 20:826 (1977); H. Singh, S. Sharma,R. N. Iyer, Ind. J. Chem., 15B:73 (1977); S. K. Dubey, A. K. Singh, H.Singh, S. Sharma, R. N. Iyer, J. Med. Chem., 37:999 (1994). The compoundof formula E-1 is coupled with the compound of formula E-2 (using PCl₃,xylenes, at reflux, for 18 hr) to yield the compound of formula E-3wherein X is —H (which is the final compound of Example 5 below) or X is—Br (which is the final compound of Example 6 below). (X in formula E-1is the same as X in formula E-3.) Chart E is the preferred couplingmethod for heterocyclic amines.

Chart F

The required thiazolones of formula F-3 are prepared in three steps fromcommercially available acids of formula F-1 as follows: the compound offormula F-1 is first treated with P_((red)) in Br and is then treatedwith AcCl in methanol to yield the compound of formula F-2. Thiscompound is then reacted with thiourea at ethanol at reflux to yield thecompound of formula F-3. T. Sohda et al., Chem. Pharm. Bull., Vol. 30,No. 10, pages 3601-3616 (1982).

Chart G

Anilines are also coupled in low to moderate yields under the conditionsof Chart E. Thus, the compound of formula G-1 is coupled with thecompound of formula G-2 (using PCl₃, xylenes, at reflux, for 18 hours)to yield the compound of formula G-3. (R¹ in formula G-1 is the same asR¹ in formula G-3.) The compound of formula G-3 wherein R¹ is —H is thefinal compound of Example 3 below; the compound of formula G-3 whereinR¹ is —Br is the final compound of Example 4 below; and the compound offormula G-3 wherein R¹ is —Cl is the final compound of Example 15 below.The coupling conditions of this reaction are preferred when anilines areused.

Chart H

Chart H discloses another method of coupling which is used in thecondensation of benzylamines, although the yields are lower than foundfor the EDC couplings. The compound of formula H-1 is coupled with thecompound of formula H-2 (using PCl₃, xylenes, at reflux for 18 hr) toyield the compound of formula H-3, which is the final compound ofExample 1 below.

Chart I

Other heterocyclic amines are also condensed with quinoline carboxylicacids under these conditions. The quinoline carboxylic acid of formulaI-1 (which was prepared in Chart A above) is coupled with theappropriate heterocyclic amine of formula I-2,I-4,I-6 or I-8 (usingPCl₃, xylenes, at reflux, for 18 hours) to yield the compound of formulaI-3, I-5, I-7 or I-9, respectively. The compound of formula 1-3 is thefinal compound of Example 2 below; the compound of formula I-5 is thefinal compound of Example 7 below; the compound of formula I-7 is thecompound of Example 13 below which is useful as an intermediate; and thecompound of formula I-9 is the final compound of Example 14 below.

Chart J

The preparation of the starting materials is accomplished byO-methylation of commercially-available 5,7-dihalo-8-hydroxyquinolinesaccording to the procedure of R. A. W. Johnstone and M. E. Rose inTetrahedron, vol. 35, page 21169 (1979). The compound of formula J-1 istreated with t-butyllithium or n-butyllithium at low temperature inether/toluene, then exposed to sulfur dioxide gas to prepare thecompound of formula J-2. Conversion of the compound of formula J-2 tothe sulfonyl chloride of formula J-3 is accomplished by treatment withN-chlorosuccinimide (CH₂Cl₂, 3 hr). The sulfonamide of formula J-4 isthen prepared by reaction of the sulfonyl chloride of formula J-3 with 1equivalent of a primary amine of the formula R²NH₂ and 2 equivalents ofpyridine in CH₂Cl₂ (15 hr). Finally, the compound of formula J-5 isprepared using either excess pyridinium hydrochloride (220° C., 10 min)or excess boron tribromide (CH₂Cl₂, 1.5 hr).

Chart K

Compounds of the structure K-3 are prepared from commercially-available5,7-dihalo-8-hydroxyquinolines (K-1) in two steps. Formation of thesilylether intermediates K-2 is accomplished by reaction of the8-hydroxyquinolines K-1 with chlorotrialkylsilanes in the presence ofimidazole and DMF at room temperature for 18-20 hours. The intermediatesare then treated with t-butyllithium or n-butyllithium at lowtemperature in THF to give the compound of formula K-3.

Chart L

To a mixture of o-anidisine of L-1 and ethyl-4,4,4-trifluoroacetoacetateof L-2 is added 6N HCl. The resulting enamine is heated in diphenyletherat 250° C. to produce 4-hydroxy-8-methoxy-2-trifluoromethylquioline ofL-3.

Chart M

The compound of M-1 is chlorinated with phosphorus oxychloride inCH₂Cl₂/DMF at room temperature. The resulting chloride of M-2 isreductively cleaved by hydrogenation in EtOH, Et₃N to give M-3. Methylether deprotection with pyridine hydrochloride at 220° C. gives2-trifluoromethyl-8-hydroxyquinoline of M-4. This material iscarboxylated to M-5 under Kolbe-Schmidt conditions. Standard amidecouplings gives the desired products of M-6.

Chart N

Alternatively, pyridine hydrochloride deprotection of N-1 gives the4,8-dihydroxyquinoline of N-2, which again is carboxylated underKolbe-Schmidt conditions to give N-3. Standard amide couplings give thedesired products of N-4.

Chart O

Aryl aldehydes of O-2 are condensed with 8-hydroxyquinaldine of O-1 at180° C. to form the 2-styryl-8-hydroxyquinolines of O-3. These arecarboxylated under Kolbe-Schmidt conditions to give O-4. Standardcouplings of the resulting acid with amines gives the desired amidesO-5.

Chart P

The preparation of the starting material of formula P-1 is accomplishedby chlorination of commercially-available 8-hydroxyquinaldine accordingto the procedure described in DE 1770065. The compound of formula P-1 isthen treated with neat flourosulfonic acid at 120° C. to form thecompound of formula P-2. Finally, the sulfonamides of formula P-3 areprepared by heating to 140° C. a mixture of 1 eq of the sulfonylflouride of formula P-2, 2 eq of the primary amine of formula RNH₂ and 3eq of N,N-diisopropylethylamine in chlorobenzene.

Chart Q

The preparation of the starting material of formula Q-1 is accomplishedby O-methylation of commercially-available5,7-dibromo-2-methyl-8-quinolinol according to the procedure of R. A. W.Johnstone and M. E. Rose in Tetrahedron, vol. 35, page 21169 (1979). Thestyrene derivative of formula Q-2 is obtained by heating the2-methylquinoline of formula Q-1 with benzaldehyde for 18 h. Theintermediate of formula Q-2 (which corresponds to J-1, R¹=CH═CHPh,X¹=X²=Br) is then advanced in four steps to the sulfonamides of formulaQ-3 (which corresponds to J-5, R¹=CH═CHPh, X¹=Cl; R²=R) following theroute previously described in Chart J.

Chart R

The preparation of the starting material of formula R-1 is accomplishedby chlorination of commercially-available 8-hydroxyquinaldine accordingto the procedure described in DE 1770065. The 7-iodo derivative offormula R-2 is then prepared by reaction of the quinoline of formula R-1with iodine monochloride in methanol. The compound of formula R-2 istreated successively with methyl magnesium bromide and n-butyllithium at−78° C. in THF, then exposed to sulfur dioxide gas to prepare thecompound of formula R-3. Conversion of the compound of formula R-3 tothe sulfonyl: chloride of formula R-4 is accomplished by treatment withN-chlorosuccinimide in methylene chloride at room temperature for 2 h.The sulfonamide of formula R-5 is then prepared by reaction of thesulfonyl chloride of formula R-4 with 2-(4-aminophenyl)ethylamine andpyridine in methylene chloride. Finally, the compound of formula R-6 isprepared by reaction of the compound of formula R-5 with excess sulfonylchloride of the formula RSO₂Cl in pyridine.

Chart S

The commercially-available 5-flouro-8-hydroxyquinoline of formula S-1 istreated with neat chlorosulfonic acid at 90-105° C. to form the sulfonylchloride of formula S-2. The sulfonamide of formula S-3 is then preparedby reaction of 1 eq of the sulfonyl chloride of formula S-2 with 3 eq ofbenzylamine in THF.

Chart T

Commercially available 8-hydroxyquinoline (T-1) is converted to the7-carboxylic acid (T-2) by heating at 175° C. in the presence ofpotassium carbonate under 800 psi carbon dioxide gas for 7 days. Theacid is then condensed with various aliphatic amines after activationwith either 1,1′-carbonyldiimidazole, or alternatively1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 1-hydroxybenzotriazoleto afford the desired amides of the formula T-3. The above amides areprepared either as discrete analogues or as part of a parallel synthesisblock.

Chart U

Anhydride U-1 is prepared from 8-hydroxy-7-quinoline carboxylic acidusing 2,2,2-trichloroethyl chloroformate and diisopropylethylamine. Thepurity of the starting materials is crucial for this reaction tosucceed; particularly, any trace of any metalic cations but alkalications, or Lewis acids, has to be avoided, as they lead to aninhibition of the reaction as well as to docarboxylation of anhydrideU-1, probably through a chelation of both starting material and product;during the whole course of the reaction, strictly basic conditions haveto be maintained, acidic conditions favoring a decarboxylation of theproduct as well. Ester U-3 is prepared from 8-hydroxy-7-quinolinecarboxylic acid as well, the 8-hydroxy substituent being first protectedto ester U-2 according to a literature procedure (German Patent No.540842, Dec. 10, 1931) and subsequent activation of the 7-carboxylicacid as its fluoride, using cyanuric fluoride and diisopropylethylamine.

Chart V

N-Aryl-8-hydroxy-7-quinolinecarboxamides V-4-14 are prepared as singlecompounds from anhydride U-1 (Chart U) following GP II described below.Both amide coupling and deprotection of the 8-hydroxy substituent can berealized in a single step with primary amines, provided some traces ofwater are present in the reaction mixture. (No water needs to be added;water coming from glassware and used solvents is enough to ensure acomplete deprotectino, at least on small scale.) Probably, the amidefunction of the still protected intermediate is nucleophilic enough toattack the carbonate at the 7-position via a six-membered ring;subsequent hydrolysis, catalyzed by pyridinium chloride, leads to thedesired amides. Similarly, N-Aryl-8-hydroxy-7-quinolinecarboxamidesV-21-36 are prepared by parallel synthesis from anhydride U-1, followingGP III described below. N-Aryl-8-hydroxy-7-quinolinecarboxamides V-15-20are prepared as single compounds following GP IV described below fromester U-3 (Chart U). After the coupling step is achieved (6 h to 5 daysdepending on the amine), methanol is added, which leads to thedeprotection of the 8-hydroxy substituent within 6 to 24 h.N-aryl-8-hydroxyquinoline-7-carboxamides V-17-20 as well as V-37-94 arealso prepared by parallel synthesis from ester U-3, following GP Vdescribed below.

When parallel synthesis is used, some impurities appear occasionallybesides the desired product, mainly the carbamate resulting from anattack of the amine at the carbonate positions when anhydride U-1 isinvolved, or methyl 8-hydroxy-7-quinoline carboxylate after methanolictreatment of the reaction mixture from ester U-3.

Chart W

The synthesis of 2-amino-5-alkyl-1,3,4-thiadiazoles W-95-98, W-100-102,W-105, W-108 and X-109-117, which are to be coupled with the activated8-hydroxy-7-quinoline carboxylic acid derivatives U-1 or U-3 (refer toChart U) to afford the corresponding8-hydroxy-N-(1,3,4-thiadiazol-2-yl)-7-quinolinecarboxamides X-118-136,required one to four steps. 2-Amino-5-bromo-1,3,4-thiadiazole W-95 isprepared through bromination of commercially available2-amino-1,3,4-thiadiazole. Thiadiazole derivatives W-96-98 are preparedthrough direct bromide displacement of thiadiazole W-95 with thecorresponding amines. Using the same strategy, nitrile W-100 is preparedfrom aminonitrile W-99, itself prepared from piperonal through aStrecker synthesis. Displacement of the bromide of thiadiazole W-95 withL- and D-phenylalanine methyl esters leads to esters W-101 and W-102,though in low yields. Known literature procedures are used to prepareamino acids W-103 and W-106, of which acid groups are converted into thecorresponding tert-butyl esters (compounds W-104 and W-107) by standardprocedures; subsequent bromide displacement as last step affords estersW-105 and W-108.

Chart X

Bromide displacement with commercially available piperonyl amine leadsto thiadiazole W-109; similarly, using some amino acid tert-butyl estersleads to esters X-110 to X-117.

Chart Y

These thiadiazoles, as well as commercially available2-amino-5-(trifluoromethyl)-1,3,4-thiadiazole, are then coupled usingthe same methodology as described for the amides V-4-20 from anhydrideU-1 or ester U-3 to give amides Y-118-125 or y-126-136, respectively.Depending on the applied work-up procedure, these compounds are isolatedas the free compounds, as the hydrochloride salt or as a hydrate.

Chart Z

The tert-butyl esters are hydrolyzed in selected examples to yield acidsZ-137-139. These acids are isolated as their correspondinghydrotrifluoroacetates.

Chart AA

N-(5-alkylamino-1,3,4-thiadiazol-2-yl)-8-hydroxy-7-quinolinesulfonamidesare prepared from the corresponding thiadiazoles and8-hydroxy-7-quinolinesulfonyl chloride AA-C, prepared in two steps froma 8-hydroxy-7-halogenoquinoline AA-A.

It will be apparent to those skilled in the art that the describedsynthetic procedures are merely representative in nature and thatalternative synthetic processes are known to one of ordinary skill inorganic chemistry.

The compounds of the present invention and pharmaceutically acceptablesalts thereof are useful as antiviral agents. Thus, these compounds areuseful to combat viral infections in animals, including man.Specifically, these compounds have anti-viral activity against theherpes virus, cytomegalovirus (CMV). Many of these compounds are alsoactive against other herpes viruses, such as the varicella zoster virus,the Epstein-Barr virus, the herpes simplex virus, and the human herpesvirus type 8 (HHV-8).

Also, while many of the compounds of the present invention have shownactivity against the CMV polymerase, these compounds may be activeagainst the cytomegalovirus by this or other mechanisms of action. Thus,the description below of these compounds' activity against the CMVpolymerase is not meant to limit the present invention to a specificmechanism of action.

The compounds of the present invention have shown activity in one ormore of the assays described below. All of these assays are indicativeof a compound's activity and thus of its use as an anti-viral agent.

The HCMV polymerase assay is performed using a scintillation proximityassay (SPA) as described in several references, such as N. D. Cook, etal., Pharmaceutical Manufacturing International, pages 49-53 (1992); K.Takeuchi, laboratory Practice, September issue (1992); U.S. Pat. No.4,568,649 (1986); which are incorporated by reference herein. Reactionsare performed in 96-well plates. The assay is conducted in 100 μl volumewith 5.4 mM HEPES (pH 7.5), 11.7 mM KCl, 4.5 mM MgCl₂, 0.36 mg/ml BSA,and 90 nM ³H-dTTP. Assays are run with and without CHAPS,(3-[(3-Cholamidopropyl)-dimethylammonio]-1-propane-sulfonate) at a finalconcentration of 2 mM. HCMV is diluted in enzyme dilution buffercontaining 50% glycerol, 250 mM NaCl, 10 mM HEPES (pH 7.5), 100 μg/mlBSA, and 0.01% sodium azide. The HCMV polymerase, which is expressed inrecombinant baculovirus-infected SF-9 cells and purified according toliterature procedures, is added at 10% (or 10 μl) of the final reactionvolume, i.e., 100 μl. Compounds are diluted in 50% DMSO and 10 μl areadded to each well. Control wells contain an equivalent concentration ofDMSO. Unless noted otherwise, reactions are initiated via the additionof 6 nM biotinylated poly(dA)-oligo(dT) template/primer to reactionmixtures containing the enzyme, substrate, and compounds of interest.Plates are incubated in a 25° C. or 37° C. H₂₀ bath and terminated viathe addition of 40 μl/reaction of 0.5 M EDTA (pH 8) per well. Reactionsare terminated within the time-frame during which substrateincorporation is linear and varied depending upon the enzyme andconditions used, i.e., 30 min. for HCMV polymerase. Ten μl ofstreptavidin-SPA beads (20 mg/ml in PBS/10% glycerol) are addedfollowing termination of the reaction. Plates are incubated 10 min. at37° C., then equilibrated to room temperature, and counted on a PackardTopcount. Linear regressions are performed and IC₅₀'s are calculatedusing computer software. Results of the testing of compounds of thepresent invention in this assay are shown in Tables 1, 2, 5, 9, 10, 11,13 (except for the last compound which was tested under modifiedconditions) and 14 below.

A modified version of the above HCMV polymerase assay is performed asdescribed above, but with the following changes: Compounds are dilutedin 100% DMSO until final dilution into assay buffer. In the previousassay, compounds are diluted in 50% DMSO. 4.5 mM dithiotherotol (DTT) isadded to the polymerase buffer. Also, a different lot of CMV polymeraseis used, which appears to be more active resulting in a more rapidpolymerase reaction. Results of the testing of compounds of the presentinvention in this assay are shown in Tables 3, 6 and 7 below.

Compounds are tested for direct antiviral activity against HCMV using acell culture based assay. An ELISA (enzyme linked immunosorbant assay)format is used as described in W. A. Tatarowicz, N. S. Lurain and K. D.Thompson, J. Virol. Meth., 35:207-215 (1991). Human foreskin fibroblastcells are infected with HCMV at a multiplicity of 0.025 plaque formingunits per microtiter plate well for a period of 90 minutes. The virusinocula is removed and a suspension of test compound prepared in tissueculture media is added for a period of 4 days. The growth media isaspirated and replaced with 95% ethanol to allow fixation of virusinfected cultures. The ethanol is removed and the wells are washed twicewith saline. A solution of 2% (try fat milk, 1% bovine sera albuminprepared in saline is added to wells to allow for non-specific bindingof protein material to plastic surfaces for 1 hr. Murine monoclonalantibody prepared in saline directed against the late (65 KD) matrixprotein of HCMV is added to test wells for 1 hr. The wells are washedtwice and antibody, conjugated with the enzyme horse radish peroxidase,with specificity against murine IgG is added to test wells for 1 hr.Test wells are washed three times with saline. A solution of o-phenylenediamine, a substrate for horse radish peroxidase is added for 15 minutesat which time enzymatic conversion occurs indicating reactivity of theenzyme with its substrate. This conversion is evident as a colorreaction which was spectrophoretically monitored at 490 nm. Theintensity of the color indirectly reflects the presence of antibodydirected against the viral 65 KD matrix antigen. The presence of theviral matrix antigen refects the amount of HCMV replication. Thus, testwells, in which little viral replication has occurred, would have littleor no antibody binding and are present with low levels of color.Non-infected wells serve as the assay background control. Results of thetesting of compounds of the present invention in this assay are shown inTables 4, 7 and 12 below.

These compounds of the present invention are administered in apharmaceutical composition containing the compound in combination with asuitable excipient, the composition being useful in combating viralinfections. Pharmaceutical compositions containing a compoundappropriate for antiviral use are prepared by methods and containexcipients which are well known in the art. A generally recognizedcompendium of such methods and ingredients is Remington's PharmaceuticalSciences by E. W. Martin (Mark Publ. Co., 15th Ed., 1975), which ishereby incorporated by reference herein.

The compounds of the present invention are administered parenterally(for example, by intravenous, intraperitoneal or intramuscularinjection), topically, orally, or rectally, depending on whether thepreparation is used to treat internal or external viral infections.

For internal infections, the compositions are administered orally orparenterally at dose levels, calculated as the free base, of about 0.1to 300 mg/kg, preferably 1.0 to 30 mg/kg of mammal body weight, and areused in man in a unit dosage form, administered one to four times dailyin the amount of 1 to 1000 mg per unit (lose.

For parenteral administration or for administration as drops, as for eyeinfections, the compounds are presented in aqueous solution in aconcentration of from about 0.1 to 10%, more preferably about 0.1 to 7%.The solution may contain other ingredients, such as emulsifiers,antioxidants or buffers.

The exact regimen for administration of the compounds and compositionsdisclosed herein will necessarily be dependent upon the needs of theindividual subject being treated, the type of treatment and, of course,the judgment of the attending practitioner.

The following compounds of the present invention are preferred:

N-[5-[(4-Chlorophenyl)methyl]-1,3,4-thiadiazol-2-yl]-8-hydroxy-7-quinolinecarboxamide;

5-Bromo-N-(4-chlorophenyl)-8-hydroxy-7-quinolinecarboxamide;

5-Chloro-N-(4-chlorophenyl)-8-hydroxy-7-quinolinecarboxamide;

N-[(4-Chlorophenyl)methyl]-8-hydroxy-2-[2-(4-methoxyphenyl)ethenyl]-7-quinolinecarboxamide;

8-Hydroxy-N-(2-hydroxy-2-phenylethyl)-2-(2-phenylethenyl)-7-quinolinecarboxamide;

N-[(4-Chlorophenyl)methyl]-8-hydroxy-2-(2-phenylethenyl)-7-quinolinecarboxamide;

8-Hydroxy-2-(2-phenylethenyl)-N-[2-(phenylthio)ethyl]-7-quinolinecarboxamide;

8-Hydroxy-N-(2-hydroxy-2-phenylethyl)-2-[2-(4-methoxyphenyl)ethenyl]-7-quinolinecarboxamide;

N-[(4-Chlorophenyl)methyl]-2-[2-(2-furyl)ethenyl]-8-hydroxy-7-quinolinecarboxamide;

5-chloro-8-hydroxy-2-methyl-N-(3-phenylpropyl)-7-quinolinecarboxamide;

5-chloro-8-hydroxy-2-methyl-N-[(2-phenylthio)ethyl]-7-quinolinecarboxamide;

8-hydroxy-N-[5-[4-[(1-methylethyl)phenylsulfonyl]amino]pentyl]-7-quinolinecarboxamide;

8-hydroxy-N-(cyanomethyl)-7-quinolinecarboxamide;

8-hydroxy-N-(2-hydroxy-2-phenylethyl)-2-[2-(4-methoxyphenyl)ethyl]-7-quinolinecarboxamide;

N-(2,2-Diphenylethyl)-8-hydroxy-7-quinolinecarboxamide;

N-(3,3-Diphenylpropyl)-8-hydroxy-7-quinolinecarboxamide;

8-Hydroxy-N-(cis-myrtanyl)-7-quinolinecarboxamide;

8-1-Hydroxy-N-(diphenylmethyl)-7-quinolinecarboxamide;

8-Hydroxy-N-(2-octyl)-7-quinolinecarboxamide;

N-[2-((1R,2S)-1,2-Diphenyl-1-hydroxy)ethyl]-8-hydroxy-7-quinolinecarboxamide;

8-Hydroxy-N-nonyl-7-quinolinecarboxamide;

N-(4-tert-Butylcyclohexyl)-8-hydroxy-7-quinolinecarboxamide;

R-8-Hydroxy-N-[1-(1-naphthyl)ethyl]-7-quinolinecarboxamide;

S—N-[1-(4-Bromophenyl)ethyl]-8-hydroxy-7-quinolinecarboxamide;

N-[2-((1S,2R)-1,2-Diphenyl-1-hydroxy)ethyl]-8-hydroxy-7-quinolinecarboxamide;

S-8-Hydroxy-N-[1-(1-naphthyl)ethyl]-7-quinolinecarboxamide;

N-[(2-Chloro-6-phenoxy-phenyl)methyl]-8-hydroxy-7-quinolinecarboxamide;

S-8-Hydroxy-N-[2-(1-hydroxy-3-[4-hydroxyphenyl])propyl]-7-quinolinecarboxamide;

8-Hydroxy-N-undecyl-7-quinolinecarboxamide;

8-Hydroxy-N-(2-methylcyclohexyl)-7-quinolinecarboxamide1e;

N-[1-(2-Ethyl)hexyl]-8-hydroxy-7-quinolinecarboxamide;

8-Hydroxy-N-(1-naphthalenylmethyl)-7-quinolinecarboxamide;

8-Hydroxy-N-[2-(2-[4-phenoxy]phenyl)ethyl]-7-quinolinecarboxamide;

R—N-[1-(4-Bromophenyl)ethyl]-8-hydroxy-7-quinolinecarboxamide;

S—O-Benzyl-N-[7-(7-Carboxy-8-hydroxy)quinolyl]-tyrosine, methyl ester;

N-[2-(4-Bromophenyl)ethyl]-8-hydroxy-7-quinolinecarboxamide;

N-(4-Cyanophenyl)-8-hydroxy-7-quinolinecarboxamide monohydrochloride;

N-(3-Chlorophenyl)-8-hydroxy-7-quinolinecarboxamide monohydrochloride;

N-Fluoren-2-yl-8-hydroxy-7-quinolinecarboxamide monohydrochloride;

8-Hydroxy-N-{4-[(indazo-6-ylamino)sulfonyl]phenyl}-7-quinolinecarboxamidemonohydrochloride;

N-(3-Benzoxyphenyl)-8-hydroxy-7-quinolinecarboxamide monohydrochloride;

N-(4-Benzoxyphenyl)-8-hydroxy-7-quinolinecarboxamide monohydrochloride;

8-Hydroxy-N-[4-(4-nitrophonoxy)phenyl]-7-quinolinecarboxamidemonohydrochloride;

8-1Hydroxy-N-naphth-1-yl-7-quinolinecarboxamide;

N-(2-Chloro-4-nitrophenyl)-8-hydroxy-7-quinolinecarboxamide;

N-Biphen-2-yl-8-hydroxy-7-quinolinecarboxamide;

N-(4-Chloro-2-methylphenyl)-8-hydroxy-7-quinolinecarboxamide;

8-Hydroxy-N-(4-propylphenyl)-7-quinolinecarboxamide;

8-Hydroxy-N-[4-(hydroxymethyl)phenyl]-7-quinolinecarboxamide;

8-Hydroxy-N-indazol-5-yl-7-quinolinecarboxamide(1e;

8-Hydroxy-N-(5-iodo-2-(methylphenyl)-7-quinolinecarboxamide;

8-Hydroxy-N-[5-(2-phenylethyl)amino-1,3,4-thiadiazol-2-yl-7-quinolinecarboxamide monohydrochloride;

N-[5-(Butylamino)-1,3,4-thiadiazol-2-yl]-8-hydroxy-7-quinolinecarboxamidemonohydrochloride;

5-Bromo-N-[(4-chlorophenyl)methyl]-8-hydroxy-7-quinolinecarboxamide;

5-Chloro-N-[(4-chlorophenyl)methyl]-8-hydroxy-7-quinolinecarboxamide;

N-Heptyl-8-hydroxy-2-[2-(4-methoxyphenyl)ethenyl]-7-quinolinecarboxamide;

N-Heptyl-8-hydroxy-2-(2-phenylethenyl)-7-quinolinecarboxamide;

8-Hydroxy-2-[2-(4-methoxyphenyl)ethenyl]-N-[2-(phenylthio)ethyl]-7-quinolinecarboxamide;

5-Chloro-N-[(4-chlorophenyl)methyl]-8-hydroxy-2-methyl-7-quinolinecarboxamide;

N-[(4-Chlorophenyl)methyl]-8-hydroxy-5-nitro-7-quinolinecarboxamide;

N-[5-[3-(4-Chlorophenyl)methyl]-4,5-dihydro-4-oxo-2-thiazolyl]-8-hydroxy-7-quinolinecarboxamide;

(E)-8-Hydroxy-2-(2-phenylethenyl)-N-(3-phenylpropyl)-7-quinolinecarboxamide;

N-{5-[(1,3-Benzodioxol-5-ylcyanomethyl)amino]-1,3,4-thiadiazol-2-yl}-8-hydroxy-7-quinolinecarboxamidemonohydrochloride;

N-[5-({1,3-Benzodioxol-5-yl-[(tert-butoxy)carbonyl]methyl}amino)-1,3,4-thiadiazol-2-yl]-8-hydroxy-7-quinolinecarboxamidesemihydrate;

N-[5-({1,3-Benzodioxol-4-yl-[(tert-butoxy)carbonyl]methyl}amino)-1,3,4-thiadiazol-2-yl]-8-hydroxy-7-quinolinecarboxamidesemihydrate;

(S)—N-[5-({[(tert-Butoxy)carbonyl]-[4-hydroxybenzyl]methyl}amino)-1,3,4-thiadiazol-2-yl]-8-hydroxy-7-quinolinecarboxamide;

(S)—N-[5-({5-[Benzoxy]amido-1-[(tert-butoxy)carbonyl]pentyl}amino)-1,3,4-thiadiazol-2-yl]-8-hydroxy-7-quinolinecarboxamide;

(S)—N-[5-({-[(tert-Butoxy)carbonyl]-2-indol-3-ylethyl}amino)-1,3,4-thiadiazol-2yl]-8-hydroxy-7-quinolinecarboxamidemonohydrate; and

(S)—N-[5-({1-[(tert-Butoxy)carbonyl]-2-[4-(tert-butoxy)phenyl]ethyl}amino)-1,3,4-thiadiazol-2-yl]-8-hydroxy-7-quinolinecarboxamidemonohydrate.

The following sulfonamide compounds of the present invention arepreferred:

5-Chloro-8-hydroxy-2-methyl-N-[2-(phenylthio)ethyl]-7-quinolinesulfonamide;

5-Chloro-N-(4-chlorophenyl)-8-hydroxy-2-methyl-7-quinolinesulfonamide;

5-Chloro-N-[4-fluorophenyl)methyl]-8-hydroxy-2-methyl-7-quinolinesulfonamide;

5-Chloro-8-hydroxy-2-methyl-N-(1-naphthalenylmethyl)-7-quinolinesulfonamide;

5-Chloro-N-(cyclohexylmethyl)-8-hydroxy-2-methyl-7-quinolinesulfonamide;

5-Chloro-8-hydroxy-2-methyl-N-(3-phenylpropyl)-7-quinolinesulfonamide;

5-Chloro-8-hydroxy-2-methyl-N-(2-phenoxyethyl)-7-quinolinesulfonamide;

5-Chloro-N-(diphenylmethyl)-8-hydroxy-2-methyl-7-quinolinesulfonamide;

(R)-5-Chloro-8-hydroxy-2-methyl-N-(1-phenylethyl)-7-quinolinesulfonamide;

(S)-5-Chloro-8-hydroxy-2-methyl-N-(l-phenylethyl)-7-quinolinesulfonamide;

5-Chloro-N-[2-(4-chlorophenyl)ethyl]-8-hydroxy-7-quinolinesulfonamide;

5-Bromo-8-hydroxy-N-(phenylmethyl)-7-quinolinesulfonamide;

5-Chloro-N-[2-(2,4-dichlorophenyl)ethyl]-8-hydroxy-2-methyl-7-quinolinesulfonamide;

(E)-5-Chloro-8-hydroxy-2-(2-phenylethenyl)-N-[²-(phenylthio)ethyl]-7-quinolinesulfonamide;and

5-Chloro-8-hydroxy-2-methyl-N-[2-[41(phenylsulfonyl)amino]phenyl]ethyl]-7-quinolinesulfonamide.

DESCRIPTION OF PREFERRED EMBODIMENTS Preparation 18-Hydroxyquinoline-7-carboxylic acid (Formula A-2 wherein R¹ is —H andR² is —H) Refer to Chart A

8-Hydroxyquinoline (50.0 g) and potassium carbonate (142.8 g) are mixedtogether in a stainless steel bomb and heated at 170° C. under 1200p.s.i. CO₂ for 7 days. The reaction is then cooled and the resultingsolid is partitioned between water (6 L) and EtOAc (1 L). The organiclayer is extracted with water (2×300 mL). The combined aqueous layersare extracted with EtOAc (3×500 mL). The aqueous layer is then acidifiedto pH 4.5 with conc. HCl. The resulting solid is collected, dried andtriturated with i-PrOH to yield 51.97 g of the title compound as a tansolid.

Physical characteristics are as follows:

¹H NMR (300 MHz, DMSO) δ8.89, 8.58, 7.89, 7.78, 7.28.

EXAMPLE 1 N-[(4-Chlorophenyl)methyl]-8-hydroxy-7-quinolinecarboxamide(Formula H-3) Refer to Chart H

A solution of 8-hydroxyquinoline-7-carboxylic acid (0.250 g) ofPreparation 1 and 4-chlorobenzylamine (0.187 g) in 25 mL xylenes isheated to reflux. To this is added dropwise PCl₃ (0.073 g). Refluxing iscontinued overnight. The reaction is then cooled and water is added todestroy excess PCl₃. The resulting solid is collected and recrystallizedfrom EtOAc/hexanes to yield 0.088 g of the title product as a yellowsolid.

Physical characteristics are as follows:

MP 162-165 ° C.

¹H NMR (300 MHz, DMSO) δ9.46, 8.93, 8.43, 8.03, 7.70, 7.46, 7.39, 4.56.

¹³C NMR (75 MHz, DMSO) δ168.5, 156.8, 149.2, 138.6, 137.5, 132.0, 129.7,128.8, 125.8, 124.1, 117.5, 113.2, 42.5.

IR (mull) 3081, 1964, 1932, 1635, 1610, 1601, 1577, 1558, 1500, 1492,1325, 1295, 846, 836, 800 cm⁻¹.

MS (FAB) m/z 313 (M+H), 315, 314, 313, 312, 173, 172, 69, 57, 55, 43.

HRMS (EI) found 312.0669.

EXAMPLE 2N-[5-[(4-Chlorophenyl)methyl]-1,3,4-thiadiazol-2-yl]-8-hydroxy-7-quinolinecarboxamide(Formula 1-3) Refer to Chart I

A solution of 8-hydroxyquinoline-7-carboxylic acid (0.236 g) ofPreparation 1 and 2-amino-5-(4-chlorobenzyl)thiadiazole (0.282 g) in 25mL xylenes is heated to reflux. To this is added dropwise PCl₃ (0.069g). Refluxing is continued overnight. The reaction is then cooled andwater is added to destroy excess PCl₃. The resulting solid is collected,dried and recrystallized HOAc to yield 0.079 g of the title product as agold solid.

Physical characteristics are as follows:

MP 276-278° C.

¹H NMR (300 MHz, DMSO) δ8.87, 8.75, 8.04, 7.88, 7.39, 7.17, 4.37.

IR (mull) 1661, 1608, 1567, 1537, 1489, 1422, 1292, 1218, 1212, 819,810, 789, 740, 652, 613 cm⁻¹.

MS (EI) m/z 396 (M+), 398, 397, 396, 173, 172, 171, 125, 116, 89, 63(4).

HRMS (EI) found 396.0471.

EXAMPLE 3 N-(4-Chlorophenyl)-8-hydroxy-7-quinolinecarboxamide (FormulaG-3 wherein R¹ is —H) Refer to Chart G

A solution of 8-hydroxyquinoline-7-carboxylic acid (3.78 g) ofPreparation 1 and 4-chloroaniline (2.55 g) in 250 mL xylenes is heatedto reflux. To this is added dropwise PCl₃ (1.37 g). Refluxing iscontinued overnight. The reaction is then cooled and water is added todestroy excess PCl. The resulting solid is collected, washed with waterand dried. The crude product is recrystallized from EtOAc/hexanes toyield 1.96 g of the title product as an orange solid.

Physical characteristics are as follows:

MP 207-209° C.

¹H NMR (300 MHz, DMSO) δ11.15, 8.91, 8.47, 8.00, 7.77, 7.71, 7.40, 7.39.

¹³C NMR (75 MHz, DMSO) δ165.8, 156.0, 147.9, 138.5, 138.4, 138.2, 131.3,129.2, 127.7, 127.6, 123.9, 122.1, 116.1, 115.9.

IR (mull) 3048, 1996, 1939, 1659, 1588, 1539, 1531, 1485, 1397, 1288,1253, 1235, 1215, 809, 745 cm⁻¹.

MS (EI) m/z 298 (M+), 300, 299, 298, 173, 172, 127, 117, 116, 89, 63.

HRMS (EI) found 298.0518.

Anal. found: C, 64.39; H, 3.68; N, 9.32; Cl, 11.82.

EXAMPLE 4 5-Bromo-N-(4-chlorophenyl)-8-hydroxy-7-quinolinecarboxamide(Formula G-3 wherein R¹ is —Br) Refer to Chart G

A solution of 5-bromo-8-hydroxyquinoline-7-carboxylic acid (2.68 g) ofPreparation 2 and 4-chloroaniline (1.28 g) in 250 mL xylenes is heatedto reflux. To this is added dropwise PCl₈ (0.69 g). Refluxing iscontinued overnight. The reaction is then cooled and water is added todestroy excess PCl₃. The resulting solid is collected, washed with waterand dried. The crude product is recrystallized from EtOAc/hexanes toyield 1.97 g of the title product as an orange solid.

Physical characteristics are as follows:

MP 213-215° C.

¹H NMR (300 MHz, DMSO) δ10.99, 9.00, 8.55, 8.25, 7.87, 7.75, 7.42.

¹³C NMR (75 MHz, DMSO) δ164.5, 155.6, 149.1, 139.7, 137.9, 136.9, 130.5,129.6, 129.3, 128.0, 125.4, 122.2, 117.2, 107.4.

IR (mull) 2043, 1957, 1926, 1658, 1594, 1558, 1552, 1521, 1493, 1480,1400, 1395, 1291, 807, 634 cm⁻¹.

MS (EI) m/z 376 (M+), 378, 376, 252, 251, 250, 196, 194, 129, 127, 115;

HRMS (EI) found 375.9618.

Anal. found: C, 50.15; H, 2.60; N, 7.27; Br, 20.85; Cl, 9.23.

Preparation 2 5-Bromo-8-hydroxyquinoline-7-carboxylic acid (Formula B-2)Refer to Chart B

8-Hydroxyquinoline-7-carboxylic acid (1.00 g) is suspended in 25 mLacetic acid. To this is added bromine (0.845 g) dropwise. The mixture isheated to reflux for 1 h, then poured into cold water. The resultingsolid is collected, washed with water and dried to yield 1.43 g of thetitle product as a yellow solid.

Physical characteristics are as follows:

MP 244-246° C.

IR (mull) 3093, 2138, 1995, 1590, 1553, 1396, 1312, 1233, 1108, 911,820, 779, 767, 730, 671 cm⁻¹.

MS (EI) m/z 267 (M+), 269, 267, 251, 249, 225, 223, 195, 193, 115, 114.

HRMS (EI) found 266.9507.

Anal. found: C, 41.84; H, 2.83; N, 4.98; Br, 28.00.

EXAMPLE 5 N-[5-(4-Chlorophenyl)-4,5-dihydro-4-oxo-2-thiazolyl]-8-hydroxy-7-quinolinecarboxamide (FormulaE-3 wherein X is —Cl) Refer to Chart E

A solution of 8-hydroxyquinoline-7-carboxylic acid (0.280 g) ofPreparation 1 and 2-amino-5-(4-chlorophenyl)-4-hydroxy-1,3-thiazole(0.340 g) in 50 mL xylenes is heated to reflux. To this is addeddropwise PCl₈ (0.103 g). Refluxing is continued overnight. The reactionis then cooled and water is added to destroy excess PCl₃. The resultingsolid is collected, washed with water and dried. The crude product istriturated with HOAc to yield 0.236 g of the title product as a goldsolid.

Physical characteristics are as follows:

MP 272-276 ° C. (dec).

¹H NMR (300 MHz, DMSO) δ13.75, 8.87, 8.72, 8.09, 7.86, 7.63, 7.37, 7.23.

IR (mull) 2042, 1954, 1702, 1685, 1535, 1482, 1424, 1338, 1300, 1262,1223, 1186, 1181, 1093, 833 cm⁻¹.

MS (EI) m/z 397 (M+), 397, 241, 226, 173, 172, 171, 155, 145, 116, 89.

HRMS (EI) found 397.0278.

EXAMPLE 65-Bromo-N-[5-(4-chlorophenyl)-4,5-dihydro-4-oxo-2-thiazolyl]-8-hydroxy-7-quinolinecarboxamide(Formula E-3 wherein X is —Br) Refer to Chart E

A solution of 5-bromo-8-hydroxyquinoline-7-carboxylic acid (0.268 g) ofPreparation 2 and 2-amino-5-(4-chlorophenyl)-4-hydroxy-1,3-thiazole(0.227 g) in 50 mL xylenes is heated to reflux. To this is addeddropwise PCl₃ (0.069 g). Refluxing is continued overnight. The reactionis then cooled and water is added to destroy excess PCl₃. The resultingsolid is collected, washed with water and dried. The crude product isrecrystallized from HOAc to yield 0.055 g of the title product as anorange solid.

Physical characteristics are as follows:

MP 254-556° C. (dec).

¹H NMR (300 MHz, DMSO) δ13.25, 8.98 8.72, 8.28, 7.99, 7.63, 7.45, 7.37.

IR (mull) 3077, 1996, 1705, 1698, 1676, 1652, 1594, 1531, 1492, 1319,1306, 1262, 1218, 1170, 1093 cm⁻¹.

MS (EI) m/z 475 (M+), 252, 251, 250, 226, 157, 156, 155, 115, 114, 89.

HRMS (EI) found 474.9391.

EXAMPLE 7N-[5-(5-Bromo-2-thienyl)-2-thiazolyl]-8-hydroxy-7-quinolinecarboxamide(Formula I-5) Refer to Chart I

A solution of 8-hydroxyquinoline-7-carboxylic acid (0.43 g) ofPreparation 1 in 80 mL xylenes is heated to reflux. PCl₃ (0.12 mL) isadded dropwise and the mixture stirred for 20 minutes.2-Amino-5-(5-bromothien-2-yl)thiazole (0.62 g) is added in one portionand the reaction refluxed overnight. The reaction is cooled to roomtemperature and H₂O is added to quench excess PCl₃. The solvents areremoved and the residue is dissolved in acetic acid. A dark orange solidprecipitates upon addition of hexanes (0.28 g) to yield the titleproduct.

Physical characteristics are as follows:

MP 279-281° C. dec.

¹H NMR (300 MHz, DMSO-d₆) δ8.89, 8.71, 8.09, 7.86, 7.55, 7.38, 7.25,7.21.

¹³C NMR (75 MHz, TFA-d) δ167.26, 161.84, 153.55, 148.16, 144.66, 135.44,132.94, 131.36, 128.99, 128.85, 128.71, 127.06, 125.24, 119.44, 117.29,113.07, 109.38.

IR (mull) 3082, 1996, 1925, 1664, 1608, 1539, 1490, 1428, 1343, 1299,1273, 1230, 1212,1034, 7376.

MS (EI) m/z 431 (M+), 433, 431, 262, 260, 180, 173, 172, 117, 116, 89.

HRMS (EI) found 430.9401.

EXAMPLE 8N-[5-(3-Chlorophenyl)-4,5-dihydro-4-oxo-2-thiazolyl]-8-hydroxy-7-quinolinecarboxamide(Formula D-3) Refer to Chart D

To a solution of 8-hydroxyquinoline-7-carboxylic acid (0.284 g,) ofPreparation 1 and 2-amino-5-(3-chlorophenyl)-4-hydroxy-1,3-thiazole(0.340 g) in 20 mL DMF is added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.305 g)and 1-hydroxybenzotriazole monohydrate (0.217 g). The mixture is stirredat room temperature for 7 days. The solution is then poured into 30 mLice-water. The resulting solid is collected and dried. The crude productis triturated with hot EtOAc, then with hot i-PrOH to yield 0.182 g ofthe title product as a yellow solid.

Physical characteristics are as follows:

MP 268-272° C. (dec).

¹H NMR (300 MHz, DMSO) δ13.88, 8.87, 8.72, 8.08, 7.86, 7.73, 7.47, 7.34,7.22. 7.14.

¹³C NMR (75 MHz, DMSO) δ164.5, 160.2, 155.6, 153.8, 144.4. 142.4, 136.7,135.6, 133.9, 132.8, 131.0, 129.3, 124.7, 124.6, 124.3, 123.7, 113.6,111.8, 97.9.

IR (mull) 2047, 1996, 1945, 1703, 1684, 1571, 1536, 1423, 1300, 1261,1222, 1185, 1113, 1085, 833 cm⁻¹.

MS (EI) m/z 397 (M+), 397, 241, 213, 173, 172, 171, 145, 116, 115, 89.

HRMS (EI) found 397.0290.

Anal. found: C, 56.78; H, 3.08; N, 10.31; Cl, 8.43; S, 7.66.

EXAMPLE 95-Bromo-N-[(4-chlorophenyl)methyl]-8-hydroxy-7-quinolinecarboxamide(Formula C-3 wherein R¹ is —Br, R² is —H, and X is —Cl) Refer to Chart C

To a solution of 5-bromo-8-hydroxyquinoline-7-carboxylic acid (0.402 g)of Preparation 2 and 4-chlorobenzylamine (0.219 g) in 20 mL DMF is added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.305 g)and 1-hydroxybenzotriazole monohydrate (0.217 g). The mixture is stirredovernight. The solution is then poured into 30 mL ice-water. Theresulting solid is collected and dried to yield 0.157 g of the titleproduct as an off-white solid.

Physical characteristics are as follows:

MP 148-151° C.

¹H NMR (300 MHz, DMSO) δ9.38, 8.97, 8.44, 8.32, 7.80, 7.38, 4.55.

¹³C NMR (75 MHz, DMSO) δ167.1, 156.9, 150.3, 140.5, 138.4, 135.6, 132.0,129.8, 129.6, 129.0, 128.8, 125.5, 114.2, 108.9, 42.6.

IR (mull) 3372, 3291, 2427, 1996, 1960, 1926, 1637, 1535, 1492, 1433,1414, 1337, 931, 798, 681 cm⁻¹.

MS (EI) m/z 390 (M+), 392, 252, 251, 250, 225, 223, 142, 140, 125, 115.

HRMS (EI) found 389.9777.

Anal. found: C, 52.48; H, 3.05; N, 7.27; Br, 19.70; Cl, 9.09.

EXAMPLE 10N-[(4-Chlorophenyl)methyl]-8-hydroxy-2-methyl-7-quinolinecarboxamide(Formula C-3 wherein R¹ is —H, R² is —CH₃, and X is —Cl) Refer to ChartC

To a solution of 8-hydroxy-2-methylquinoline-7-carboxylic acid (0.305 g)of Preparation 5 and 4-chlorobenzylamine (0.219 g) in 20 mL DMF is added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.305 g)and 1-hydroxybenzotriazole monohydrate (0.217 g). The mixture is stirredovernight. The solution is then poured into 30 mL ice-water. Theresulting solid is collected and dried to yield 0.337 g of the titleproduct as an off-white solid.

Physical characteristics are as follows:

MP 95-98° C.

¹H NMR (300 MHz, DMSO) δ9.40, 8.21, 7.90, 7.51, 7.39, 7.35, 4.54, 2.67.

¹³C NMR (75 MHz, DMSO) δ169.0, 158.1, 157.2, 139.0, 138.6, 136.6, 132.0,129.7, 129.5, 128.8, 124.8, 124.3, 117.1, 112.6, 21.4, 25.1.

IR (mull) 1950, 1905, 1645, 1635, 1607, 1561, 1539, 1507, 1491, 1423,1410, 1338, 1286, 1245, 846 cm⁻¹.

MS (EI) m/z 326 (M+), 326, 187, 186, 160, 159, 131, 130, 125, 103, 77.

HRMS (EI) found 326.0829.

Anal. found: C, 65.52; H, 4.74; N, 8.57; Cl, 10.79.

EXAMPLE 115-Chloro-N-[(4-chlorophenyl)methyl]-8-hydroxy-7-quinolinecarboxamide(Formula C-3 wherein R¹ is —Cl, R² is —H, and X is —Cl) Refer to Chart C

To a solution of 5-chloro-8-hydroxyquinoline-7-carboxylic acid (0.335 g)of Preparation 3 and 4-chlorobonzylamine (0.219 g) in 20 mL DMF is added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.305 g)and 1-hydroxybenzotriazole monohydrate (0.217 g). The mixture is stirredovernight. The solution is then poured into 30 mL ice-water. Theresulting solid is collected and dried to yield 0.167 g of the titleproduct as an off-white solid.

Physical characteristics are as follows:

MP 163-166° C.

¹H NMR (300 MHz, DMSO) δ9.37, 9.00, 8.50, 8.15, 7.80, 7.38, 4.55.

¹³C NMR (75 MHz, DMSO) δ167.2, 156.3, 150.3, 140.3, 138.4, 133.1, 132.0,129.8, 128.8, 128.4, 125.5, 125.1, 119.1, 113.5, 42.6.

IR (mull) 3362, 3292, 2429, 2280, 1962, 1929, 1636, 1619, 1537, 1493,1433, 1338, 953, 799, 680 cm⁻¹.

MS (EI) m/z 346 (M+), 346, 207, 206, 181, 179, 150, 142, 140, 127, 125.

Anal. found: C, 58.59; H, 3.71; N, 8.19; Cl, 19.72.

EXAMPLE 12 8-Hydroxy-N-[(4-nitrophenyl)methyl]-7-quinolinecarboxamide(Formula C-3 wherein R¹ is —H, R² is —H, and X is —NO₂) Refer to Chart C

8-Hydroxyquinoline-7-carboxylic acid (0.51 g) of Preparation 1 is addedto 20 mL DMF. 4-Nitrobenzylamine hydrochloride (0.53 g) followed bydiisopropylethylamine (0.49 mL) is then added. After 10 minutes, allsolids go into solution. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (0.54 g) and 1-hydroxybenzotriazole monohydrate (0.38 g)are added and the reaction stirred at room temperature overnight. Thereaction is poured into 75 mL H₂O. The resulting solid is filtered anddried to give the title product (0.53 g).

Physical characteristics are as follows:

MP 210-212° C. .

¹H NMR (300 MHz, DMSO-d₆) δ9.45, 8.91, 8.35, 8.20, 7.99, 7.64, 7.61,7.43, 4.70.

¹³C NMR (75 MHz, DMSO-d₆) δ168.42, 156.84, 149.50, 147.82, 146.95,139.50, 136.63, 131.16, 128.75, 125.85, 124.04, 117.49, 113.29, 42.73.

IR (mull) 2450, 2292, 1927, 1612, 1602, 1575, 1556, 1518, 1344, 1325,1296, 1107, 855, 837, 697.

MS (electrospray) m/z 322 (M+).

Anal. found: C, 62.80; H, 4.29; N, 12.99.

EXAMPLE 13N-(6-Chloro-2-benzothiazolyl)-8-hydroxy-7-quinolinecarboxamide (FormulaI-7) Refer to Chart I

A solution of 8-hydroxyquinoline-7-carboxylic acid (0.30 g) ofPreparation 1 in 75 mL xylenes is heated to reflux. PCl₃ (0.07 mL) isadded dropwise and the mixture stirred for 15 minutes.2-Amino-6-chlorobenzothiazole (0.31 g) is added in one portion and thereaction refluxed overnight. The reaction is cooled to room temperatureand H₂O is added to quench excess PCl₃. After stirring the solution for30 minutes, a yellow solid is filtered, dried, and recrystallized fromDMSO to give the title product (0.31 g).

Physical characteristics are as follows:

MP>320° C.

¹H NMR (300 MHz, TFA-d) δ9.29, 9.23, 8.56, 8.35, 8.08, 8.01, 7.96, 7.81.

¹³C NMR (75 MHz, TFA-d) δ167.92, 163.82, 154.19, 148.65, 145.25, 135.42,133.94, 133.52, 131.34, 129.40, 128.01, 127.33, 125.86, 122.74, 120.06,117.47, 113.33.

IR (mull) 2188, 2026, 1954, 1918, 1661, 1657, 1612, 1598, 1546, 1531,1494, 1441, 1258, 1210, 809.

MS (EI) m/z 355 (M+), 357, 355, 186, 184, 173, 172, 117, 116, 89, 63.

HRMS (EI) found 355.0179.

EXAMPLE 14N-[5-(4-Chlorophenyl)-1,3,4-thiadiazol-2-yl]-8-hydroxy-7-quinolinecarboxamide(Formula I-9) Refer to Chart I.

A suspension of 8-hydroxyquinoline-7-carboxylic acid (0.236 g) ofPreparation 1 in 50 mL xylenes is heated to reflux. To this is addeddropwise PCl₃ (0.069 g). After 15 min,2-amino-5-(4-chlorophenyl)-thiadiazole (0.264 g) is added. Refluxing iscontinued overnight. The reaction is then cooled and water is added todestroy excess PCl₃. The resulting solid is collected, washed with waterand dried. The crude product is recrystallized from DMSO to yield 0.204g of the title product as a yellow-orange solid.

Physical characteristics are as follows:

¹H NMR (300 MHz, TFA) δ9.54, 9.48, 8.83, 8.59, 8.24, 7.95.

¹³C NMR (75 MHz, TFA) δ167.9, 167.3, 159.9, 153.5, 147.9, 144.5, 142.7,132.8, 130.4, 128.8, 126.6, 125.1, 121.5, 119.3.

IR (mull) 2031, 1966, 1924, 1673, 1611, 1572, 1536, 1489, 1211, 1090,1086, 829, 807, 740, 639 cm⁻¹.

MS (EI) m/z 382 (M+), 384, 383, 382, 173, 172, 155, 117, 116, 89, 63.

HRMS (EI) found 382.0018.

EXAMPLE 15 5-Chloro-N-(4-chlorophenyl)-8-hydroxy-7-quinolinecarboxamide(Formula G-3 wherein R¹ is —Cl) Refer to Chart G

A suspension of 5-chloro-8-hydroxyquinoline-7-carboxylic acid (0.224 g)of Preparation 3 in 50 mL xylene is heated to reflux. To this is addeddropwise PCl₃ (0.069 g). After 15 min, 4-chloroaniline (0.128 g) isadded. Refluxing is continued overnight. The reaction is then cooled andwater is added to destroy excess PCl₃. The resulting solid is collected,washed with water and dried. The solid is then partitioned between EtOAcand water. The aqueous layer is extracted with EtOAc (3×). The combinedorganic layers are washed with water, dried and condensed. The crudeproduct is recrystallized from EtOAc to yield 0.073 g of the titleproduct as an orange solid.

Physical characteristics are as follows:

MP 214-216° C.

¹H NMR (300 MHz, DMSO) δ10.92, 9.02, 8.59, 8.09, 7.86, 7.75, 7.41.

¹³C NMR (75 MHz, DMSO-d₆) δ164.6, 154.9, 149.2, 139.6, 137.9, 134.3,129.2, 128.3, 128.0, 126.9, 125.1, 122.2, 118.0, 116.4.

IR (mull) 2055, 1962, 1931, 1658, 1597, 1553, 1532, 1525, 1495, 1482,1402, 1393, 1293, 807, 640 cm⁻¹.

MS (EI) m/z 332 (M+), 333, 332, 208, 207, 206, 152, 150, 129, 115.

Anal. found: C, 57.60; H, 3.03; N, 8.35; Cl, 20.96.

Preparation 3 5-Chloro-8-hydroxyquinoline-7-carboxylic acid (Formula A-2wherein R¹ is —Cl and R² is —H) Refer to Chart A

5-Chloro-8-hydroxyquinoline (5.00 g) and potassium carbonate (11.54 g)are mixed together in a stainless steel bomb and heated to 170° C. under800 p.s.i. CO₂ for 7 clays. The reaction is cooled and the resultingsolid is dissolved in 800 mL water. The insoluble material is filteredand partitioned between 800 mL water and 400 mL EtOAc in a separatoryfunnel. The aqueous layer is washed with EtOAc (3×400 mL). The aqueouslayer is then acidified to pH 4.5 with conc. HCl. The resulting solid iscollected, washed with water and dried. The crude product is trituratedwith i-PrOH and dried to yield 1.481 g of the title product as a brownsolid.

Physical characteristics are as follows:

MP 285-287° C.

¹H NMR (300 MHz, DMSO) δ8.99, 8.58, 7.89, 7.78.

IR (mull) 2471, 2420, 1994, 1964, 1902, 1393, 1296, 1232, 1222, 1115,1109, 955, 923, 819, 788 cm⁻¹ .

MS (EI) m/z 222 (M+), 223, 207, 205, 181, 179, 151, 150, 149, 115, 114.

Anal. found: C, 53.63; H, 2.90; N, 6.17; Cl, 15.34.

Preparation 4 5-Fluoro-8-hydroxyquinoline-7-carboxylic acid (Formula A-2wherein R¹ is —F and R² is —H) Refer to Chart A

5-Fluoro-8-hydroxyquinoline (3.00 g) and potassium carbonate (7.62 g)are mixed together in a stainless steel bomb and heated to 170° C. under800 p.s.i. CO₂ for 7 days. The reaction is cooled and the resultingsolid is partitioned between 800 mL water and 400 mL EtOAc in aseparatory funnel. The aqueous layer is washed with EtOAc (3×400 mL).The aqueous layer is then acidified to pH 4.5 with conc. HCl and cooled.The resulting solid is collected, washed with water and dried. The crudeproduct is triturated with i-PrOH and dried to yield 1.67 g of the titleproduct as a brown solid.

Physical characteristics are as follows:

MP 277-279° C.

¹H NMR (300 MHz, DMSO) δ9.01, 8.49, 7.79, 7.57.

IR (mull) 2446, 2417, 1995, 1965, 1637, 1445, 1405, 1270, 1257, 1215,1068, 1032, 819, 785, 742 cm⁻¹.

MS (EI) m/z 207 (M+), 207, 189, 163, 161, 135, 134, 133, 132, 107, 81.

Anal. found: C, 57.95; H, 2.88; N, 6.66.

EXAMPLE 165-Fluoro-N-[[4-chlorophenyl]methyl]-8-hydroxy-7-quinolinecarboxamide(Formula C-3 wherein R¹ is —F, R² is —H, and X is —Cl) Refer to Chart C

To a solution of 5-fluoro-8-hydroxyquinoline-7-carboxylic acid (0.311 g)of Preparation 4 and 4-chlorobenzylamine (0.219 g) in 20 mL DMF is added1-(3-di-methylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.305 g)and 1-hydroxybenzotriazole monohydrate (0.217 g). The mixture is stirredovernight. The solution is then poured into 30 mL ice-water. Theresulting solid is collected and dried. The crude product isrecrystallized from EtOAc/hexanes to yield 0.207 g of the title productas an off-white solid.

Physical characteristics are as follows:

MP 184-185° C.

¹H NMR (300 MHz, DMSO) δ9.31, 9.00, 8.45, 7.82, 7.75, 7.38, 4.55.

¹³C NMR (75 MHz, DMSO-d₆) δ167.4, 153.7, 150.7, 149.4, 147.7, 139.7,138.5, 132.0, 129.8, 129.5, 128.8, 124.5, 121.5, 111.8, 108.6, 42.6.

IR (mull) 3303, 2302, 2185, 1971, 1940, 1910, 1648, 1634, 1545, 1531,1494, 1435, 1402, 1066, 798 cm⁻¹.

MS (EI) m/z 330 (M+), 330, 191, 190, 163, 142, 140, 135, 134, 125, 107.

Anal. found: C, 61.05; H, 3.74; N, 8.35; Cl, 10.56.

Preparation 5 2-Methyl-8-hydroxyquinoline-7-carboxylic acid (Formula A-2wherein R¹ is —H and R² is —CH₃) Refer to Chart A

8-1-Hydroxyquinaldine (5.0 g) and potassium carbonate (13.02 g) aremixed together in a stainless steel bomb and heated to 170° C. under 800p.s.i. CO₂ for 6 days. The reaction is then cooled and the resultingsolid is partitioned between EtOAc and water. The organic layer isextracted with water (3×). The combined aqueous layers are washed withEtOAc (3×). The aqueous layer is then acidified to pH 4.5 with conc.HCl. The resulting solid is collected, dried and recrystallized fromi-PrOH to yield 1.86 g of the title compound as a gold solid.

Physical characteristics are as follows:

MP 217-219° C.

¹H NMR (300 MHz, DMSO) δ8.54, 7.85, 7.71, 7.19, 2.79.

IR (mull) 3414, 2181, 2044, 1995, 1959, 1921, 1668, 1639, 1611, 1589,1486, 1432, 1324, 858, 757 cm⁻¹.

MS (EI) m/z 203 (M+), 203, 185, 159, 131, 130, 129, 103, 102, 77, 51.

HRMS 203.0600.

Anal. found: C, 59.53; H, 4.98; N, 6.37.

Preparation 6 5-Bromo-8-methoxy-2-methyl-7-quinolinesulfinic acid,lithium salt (Formula J-2 wherein R¹=Me and X¹=Br) Refer to Chart J

Under N₂, a flame-dried, 250-mL, three-necked flask with attachedaddition funnel and bubbler is charged with5,7-dibromo-8-methoxy-2-methyl-quinoline (3 g), ether (18 mL) andtoluene (18 mL). The flask is cooled in a dry ice/acetone bath, degassedand flushed with N₂. To facilitate stirring, additional ether (5 mL) andtoluene (5 mL) are added. The addition funnel is charged with 1.6 MnBuLi (5.6 mL) which is then added dropwise over 7 min to the thickslurry. The reaction mixture is stirred at −78° C. for 3 hrs. Sulfurdioxide is then introduced via a needle positioned directly above thereaction surface. Within 5 min, the reaction mixture becomes a paleyellow opaque solution, and SO₂ introduction is terminated. The reactionmixture is flushed with N₂, the cooling bath is removed, and thereaction mixture is allowed to warm to room temperature over 1 hr. 100mL hexane is added to aid precipitation of the solid, which is thencollected by filtration. Drying under vacuum yields 2.844 g of the titlecompound as a yellow solid.

Preparation 7 5-Bromo-8-methoxy-2-methyl-7-quinolinesulfonyl chloride(Formula J-3 wherein R¹=Me and X¹=Br) Refer to Chart J

Under N₂, a flame-dried, 250-mL, three-necked flask is charged with thetitle compound of Preparation 6 (2.844 g) and CH₂Cl₂ (45 mL). The flaskis cooled in an ice bath and N-chlorosuccinimide (1.178 g) is added inone portion. After 5 min, the cooling bath is removed and the reactionmixture is stirred for 3 hrs. The reaction mixture is then poured intoH₂O, a small amount of brine is added, and the layers are separated. Theaqueous layer is extracted with two portions CH₂Cl₂. The combinedorganic layers are washed with brine, dried over MgSO₄, filtered andconcentrated to give the title compound as a pale orange solid, which isimmediately used in the preparation of compounds of the formula J-4.

Preparation 85-Bromo-N-[(4-chlorophenyl)methyl]-8-methoxy-2-methyl-7-quinolinesulfonamide(Formula J-4 wherein R¹=Me, X¹=Br, and R²=CH₂-4-ClC₆H₄) Refer to Chart J

Under N₂, a flame-dried, 250-mL, three-necked flask is charged with4-chlorobenzylamine (980 μL), pyridine (1.3 mL), and CH₂Cl₂ (10 mL). Thetitle compound of Preparation 7 in 55 mL CH₂Cl₂ is transfered viacannula to the reaction flask and then is allowed to stir overnight atroom temperature. The reaction mixture is concentrated and the residueis taken up in toluene and concentrated twice. Purification by columnchromatography (elution with 0.5% MeOH/CH₂Cl₂) affords 1.47 g of thetitle compound as a yellow foam.

Physical characteristics are as follows:

MP 108-110° C.

¹H NMR (300 MHz, CDCl₃) δ8.43, 8.09, 7.51, 7.14-7.07, 5.50, 4.35, 4.08,2.84 ppm.

MS (ES−) m/z 453 (M−H).

EXAMPLE 175-Chloro-N-[(4-chlorophenyl)methyl]-8-hydroxy-2-methyl-7-quinolinesulfonamide(Formula J-5 wherein R¹=Me, X¹=Cl, and R²=CH₂-4-ClC₆H₄) Refer to Chart J

A flame-dried, 100-mL, one-necked flask with attached oven-driedcondensor is charged with the title compound of Preparation 8 (0.640 g)and pyridine hydrochloride (8.8 g). The reaction mixture is heated to215-220° C. for 10 min., and then is poured onto ice. It is neutralizedwith saturated aqueous NaHCO₃ and extracted with CH₂Cl₂ three times. Thecombined organic layers are washed with brine, dried over MgSO₄,filtered and concentrated. The residue is taken up in toluene andconcentrated four times. Crystallization from CH₂Cl₂/Et₂O provides 0.247g of the title compound as an off-white solid.

Physical characteristics are as follows:

MP 158-161° C. (decompose).

¹H NMR (300 MHz, CDCl) δ8.44, 7.88, 7.56, 7.13-7.05, 5.42, 4.14, 2.80ppm.

MS (ES−) m/z 394.9 (M−H).

Anal. found: C, 51.40; H, 3.73; N, 7.09.

Preparation 95-Chloro-N-[(4-chlorophenyl)methyl]-8-methoxy-7-quinolinesulfonamide(Formula J-4 wherein R¹=H, X¹=Cl, and R²=CH₂-4-ClC₆H₄) and5-Chloro-N-[(4-chlorophenyl)methyl]-2-(1,1-dimethylethyl)-8-methoxy-7-quinolinesulfonamide(Formula J-4 wherein R¹=t-Bu, X¹=Cl, and R²=CH₂-4-ClC₆H₄) Refer to ChartJ

A mixture of the title compounds is prepared according to the proceduresdescribed in Preparations 6-8 substituting5-chloro-7-iodo-8-methoxy-quinoline for5,7-dibromo-8-methoxy-2-methyl-quinoline and two equivalents of tBuLifor one equivalent of nBuLi in Preparation 6. The title compounds areseparated by column chromatography (elution with 5-10% EtOAc/hexanes and10% MeOH/CH₂Cl₂) to give 0.407 g of-Chloro-N-[(4-chlorophenyl)methyl]-8-methoxy-7-quinolinesulfonamide and0.040 g of-Chloro-N-[(4-chlorophenyl)methyl]-2-(1,1-dimethylethyl)-8-methoxy-7-quinolinesulfonamide.

Physical characteristics for-Chloro-N-[(4-chlorophenyl)methyl]-8-methoxy-7-quinolinesulfonamide areas follows:

¹H NMR (300 MHz, CDCl₃) δ9.11, 8.68, 7.70-7.66, 7.14-7.09, 5.50,4.16-4.11 ppm.

MS (ES−) m/z 394.9 (M−H).

MS (ES+) m/z 396.9 (M+H).

Physical characteristics for-Chloro-N-[(4-chlorophenyl)methyl]-2-(1,1-dimethylethyl)-8-methoxy-7-quinolinesulfonamideare as follows:

¹H NMR (300 MHz, CDCl₃) δ8.50, 7.93, 7.75, 7.16-7.09, 5.49, 4.42, 4.09,1.50 ppm.

MS (ES−) m/z 450.9 (M−H).

MS (ES+) m/z 452.9 (M+H).

EXAMPLE 185-Chloro-N-[(4-chlorophenyl)methyl]-8-hydroxy-7-quinolinesulfonamide(Formula J-5 wherein R¹=H, X¹=Cl, and R²=CH₂-4-ClC₆H₄) Refer to Chart J

Under N₂, a flame-dried, 50-mL, two-necked flask is charged with5-chloro-N-[(4-chlorophenyl)methyl]-8-methoxy-7-quinolinesulfonamide(0.322 g), which is the first title compound of Preparation 9, andCH₂Cl₂ (20 mL) and is cooled in a dry ice/acetone bath. 1.0 M BBr₃ (1.05mL) is added dropwise. The cooling bath is removed and the reactionmixture is allowed to stir for 1.5 hrs. It is then poured into 75 mL 5%NaHCO₃ aqueous solution, and the layers are separated. The aqueous layeris extracted twice with CH₂Cl₂. The combined organic layers are washedwith H₂O and then brine, dried over MgSO₄, filtered and concentrated toa brown residue. Purification by column chromatography (elution with2-5% MeOH/ CH₂Cl₂ with <1% AcOH) yields 0.037 g of the title compound asa pale yellow solid.

Physical characteristics are as follows:

MP 189-190° C. (decompose).

¹H NMR (300 MHz, CDCl₃) δ8.96, 8.67, 8.35, 7.81, 7.68, 7.09, 5.44, 4.15ppm.

IR (mull) 3302, 3088, 1586, 1506, 1492, 1326, 1151, 821, 779 cm⁻¹.

MS (EI) m/z 382 (M+) 382, 243, 179, 150, 140, 125, 115.

HRMS (EI) found 381.9917.

EXAMPLE 19 5-Chloro-N-[(4-chlorophenyl)methyl]-2-(1,1-dimethylethyl)-8-hydroxy-7-quinolinesulfonamide (Formula J-5 whereinR¹=t-Bu, X¹=Cl, and R²=CH₂-4-ClC₆H₄) Refer to Chart J

The title compound is prepared from5-Chloro-N-[(4-chlorophenyl)methyl]-2-(1,1-dimethylethyl)-8-methoxy-7-quinolinesulfonamide,which is the second title compound of Preparation 9, and 6 equivalentsof BBr₃ according to the procedure described in Example 18.Crystallization from Et₂O/hexane affords 0.035 g of the title compoundas a dark tan solid.

Physical characteristics are as follows:

MP 162-163° C. (decompose).

¹H NMR (300 MHz, CDCl₃) δ8.50, 7.91, 7.82, 7.14-7.06, 5.45, 4.16, 1.51ppm.

IR (mull) 3334, 3302, 2725, 1597, 1562, 1491, 1333, 1320, 1308, 1161,1153, 1139, 1129 cm⁻¹.

MS (EI) m/z 438 (M+) 235, 220, 218, 193, 179, 150, 140.

Anal. found: C, 54.30; H, 4.52; N, 6.23.

Preparation 105-Chloro-N-(4-chlorophenyl)-8-methoxy-7-quinolinesulfonamide (FormulaJ-4 wherein R¹=H, X¹=Cl, and R²=p-ClC₆H₄) Refer to Chart J

The title compound is prepared according to the procedures described inPreparations 6-8, substituting 5-chloro-7-iodo-8-methoxy-quinoline for5,7-dibromo-8-methoxy-2-methyl-quinoline and two equivalents of tBuLifor one equivalent of nBuLi in Preparation 6 and 4-chloroaniline for4-chlorobenzylamine in Preparation 8. Column chromatography (elutionwith 5% MeOH / CH ₂Cl₂) affords MeOH/CH₂Cl₂) affords 0.373 g of thetitle compound as a solid.

Physical characteristics are as follows:

¹H NMR (300 MHz, CDCl₃) δ9.08, 8.73, 7.66, 7.57, 7.18-7.07, 4.08 ppm.

MS (ES−) m/z 380.9 (M−H).

EXAMPLE 20 5-Chloro-N-(4-chlorophenyl)-8-hydroxy-7-quinolinesulfonamide(Formula J-5 wherein R¹=H, X¹=Cl, and R²=4-ClC₆H₄) Refer to Chart J

The title compound is prepared from5-chloro-N-(4-chlorophenyl)-8-methoxy-7-quinolinesulfonamide, which isthe first title compound of Preparation 9, and 6 equivalents of BBr₃according to the procedure described in Example 18. Crystallization fromEt₂O/hexane/CH₂Cl₂ affords 0.015 g of the title compound as a red-brownsolid.

Physical characteristics are as follows:

MP 97° C. (decompose).

¹H NMR (300 MHz, CDCl₃) δ8.94, 8.71, 8.30, 7.76, 7.70, 7.17-7.07 ppm.

MS (EI) m/z 368 (M+) 370, 368, 178, 150, 128, 127, 126, 115, 99, 63.

Preparation 115-Chloro-8-methoxy-N-(3-phenylpropyl)-7-quinolinesulfonamide (FormulaJ-4 wherein R¹=H, X¹=Cl, and R²=(CH₂)₃CH₅) Refer to Chart J

The title compound is prepared according to the procedures described inPreparations 6-8, substituting 5-chloro-7-iodo-8-methoxy-quinoline for5,7-dibromo-8-methoxy-2-methyl-quinoline and two equivalents of tBuLifor one equivalent of nBuLi in Preparation 6 and 3-phenyl-1-propylaminefor 4-chlorobenzylamine in Preparation 8. Column chromatography (elutionwith 0.5% MeOH/CH₂Cl₂) affords 0.143 g of the title compound as a solid.

Physical characteristics are as follows:

¹H NMR (CDCl₃) δ9.10, 8.74, 7.70, 7.67, 7.23-7.14, 7.05-7.02, 5.16,4.15, 3.03-2.97, 2.64-2.59, 1.86-1.77 ppm.

MS (ES−) m/z 389.0 (M−H).

EXAMPLE 21 5-Chloro-8-hydroxy-N-(3-phenylpropyl)-7-quinolinesulfonamidemonohydrobromide (Formula J-5 wherein R¹=H, X¹=Cl, and R²=(CH₂)₃C₆H₅)Refer to Chart J

The title compound is prepared from5-chloro-8-methoxy-N-(3-phenylpropyl)-7-quinolinesulfonamide, which isthe title compound of Preparation 11, and 6 equivalents of BBr₃according to the procedure described in Example 18. Crystallization fromCHCl_/acetone/EtOH affords 0.063 g of the title compound as a red-brownsolid.

Physical characteristics are as follows:

MP 210-212° C. (decompose).

¹H NMR (300 MHz, CDCl₃) δ9.35, 9.18, 8.06, 7.95, 7.27-7.12, 7.11-7.05,3.16-3.02, 2.63, 1.83 ppm.

IR (mull) 3273, 2757, 1626, 1550, 1444, 1353, 1326, 1297, 1281, 1152cm⁻¹.

MS (EI) m/z 376 (M+) 376, 258, 181, 180, 179, 178, 150, 118, 115, 91.

HRMS (EI) found 376.0631.

Anal found: C, 46.96; H, 4.09; N, 6.08.

EXAMPLE 22 5-Chloro-8-hydroxy-N-(phenylmethyl)-7-quinolinesulfonamide(Formula J-5 wherein R¹=Me, X¹=Cl, and R²=CH₂Ph) Refer to Chart J

The title compound is prepared from 5,7-dibromo-8-methoxy-quinoline,which is commercially available, according to the procedures describedin Preparations 6-8 and Example 17, substituting benzylamine for4-chlorobenzylamine. Crystallization from CH₂Cl₂/Et₂O gives 0.104 g ofthe title compound as a pale orange solid.

Physical characteristics are as follows:

MP 114-117° C.

¹H NMR (300 MHz, DMSO) δ9.06, 8.54, 8.12, 7.87, 7.77, 7.22, 7.11, 7.03,4.13 ppm.

IR (mull) 3326, 1501, 1415, 1403, 1341, 1152, 1141, 1061, 952, 811, 741,724, 675, 637, 604 cm⁻¹.

MS (EI) m/z 348 (M+).

Anal found: C, 54.88 ; H, 3.79; N, 7.90.

EXAMPLE 235-Chloro-N-[2-(4-chlorophenyl)ethyl]-8-hydroxy-7-quinolinesulfonamide(Formula J-5 wherein R¹=Me, X¹=Cl, and R²=CH₂CH₂-p-ClC₆H₄) Refer toChart J

The title compound is prepared from 5,7-dibromo-8-methoxy-quinoline,which is commercially available, according to the procedures describedin Preparations 6-8 and Example 17, substituting2-(4-chlorophenyl)ethylamine for 4-chlorobenzylamine. Crystallizationfrom CH₂Cl₂ gives 0.100 g of the title compound as a pale yellow solid.

Physical characteristics are as follows:

MP 192-194° C.

¹H NMR (300 MHz, CDCl₃) δ8.94, 8.59, 7.98, 7.72, 7.12, 7.00, 5.07, 3.26,2.79 ppm.

IR (mull) 3332, 1499, 1401, 1329, 1272, 1188, 1155, 1088, 1081, 952,824, 819, 724, 677, 633 cm⁻¹.

MS (EI) m/z 396 (M+).

Anal found: C, 51.27; H, 3.61; N, 6.98.

EXAMPLE 24 5-Bromo-8-hydroxy-N-(phenylmethyl)-7-quinolinesulfonamide(Formula J-5 wherein R¹=Me, X¹=Cl, and R²=CH₂Ph) Refer to Chart J

The title compound is prepared from 5,7-dibromo-8-methoxy-quinoline,which is commercially available, according to the procedures describedin Preparations 6-8 and Example 18, substituting benzylamine for4-chlorobenzylamine. Crystallization from CH₂Cl₂ gives 0.150 g of thetitle compound as a light peach solid.

Physical characteristics are as follows:

MP 191-192° C.

¹H NMR (300 MHz, DMSO) δ9.04, 8.47, 8.12, 7.94, 7.87, 7.22, 7.11, 7.03,4.14 ppm.

¹³C NMR (75 MHz, DMSO) δ152.3, 149.8, 139.2, 137.5, 135.2, 128.9, 128.4,127.7, 127.4, 126.6, 125.2, 123.4, 107.5, 46.1 ppm.

IR (mull) 3325, 1498, 1414, 1401, 1340, 1153, 1139, 1060, 932, 810, 791,725, 695, 674, 630 cm⁻¹.

MS (EI) m/z 392 (M+).

HRMS (EI) found 391.9813.

Anal found: C, 49.17; H, 3.59; N, 6.88.

EXAMPLE 255-Chloro-N-[2-(2,4-dichlorophenyl)ethyl]-8-hydroxy-2-methyl-7-quinolinesulfonamide(Formula J-5 wherein R¹=Me, X¹=Cl, and R²=CH₂CH₂-2,3-Cl₂C₆H₃) Refer toChart J

The title compound is prepared in two steps from5-bromo-8-methoxy-2-methyl-7-quinolinesulfonyl chloride, which is thetitle compound of Preparation 7, according to the procedures describedin Preparation 8 and Example 17, substituting 2,4-dichlorophenethylaminefor 4-chlorobenzylamine in the former procedure. Column chromatography(elution with 1-2% MeOH/CHCl₃) followed by crystallization fromCH₂Cl₂/hexane gives 0.35 g of the title compound as a yellow solid.

Physical characteristics are as follows:

MP 132-135° C.

¹H NMR (300 MHz, CDCl₃) δ8.53, 7.94, 7.59, 7.19-7.04, 5.30, 3.28, 2.92,2.88 ppm.

IR (mull) 3343, 3321, 3299, 1504, 1419, 1349, 1339, 1330, 1152, 1144,955, 824, 727, 634, 612 cm⁻¹.

MS (EI) m/z 444 (M+).

HRMS (EI) found 443.9845.

EXAMPLE 265-Chloro-8-hydroxy-2-methyl-N-[2-(phenylthio)ethyl]-7-quinolinesulfonamide(Formula J-5 wherein R¹=Me, X¹=Cl, and R²=CH₂CH₂SPh) Refer to Chart J

The title compound is prepared in two steps from5-bromo-8-methoxy-2-methyl-7-quinolinesulfonyl chloride, which is thetitle compound of Preparation 7, according to the procedures describedin Preparation 8 and Example 17, substituting 2-aminoethyl phenylsulfide for 4-chlorobenzylamine in the former procedure. Columnchromatography (elution with 1-2 % MeOH/CHCl₃) followed bycrystallization from CH₂Cl₂/hexane gives 0.40 g of the title compound asa yellow solid.

Physical characteristics are as follows:

MP 136-139° C.

¹H NMR (300 MHz, CDCl₃) δ8.43, 7.89, 7.56, 7.24-7.07, 5.60, 3.14, 3.02,2.81 ppm.

IR (mull) 3355, 3271, 1438, 1419, 1342, 1329, 1308, 1153, 1141, 1078,741, 702, 692, 632, 610 cm⁻¹.

MS (EI) m/z 408 (M+).

Anal found: C, 52.50; H, 4.14; N, 6.73; Cl, 8.77; S, 15.31.

EXAMPLE 275-Chloro-8-hydroxy-2-methyl-N-(phenylmethyl)-7-quinolinesulfonamide(Formula J-5 wherein R¹=Me, X¹=Cl, and R²=CH₂Ph) Refer to Chart J

The title compound is prepared in two steps from5-bromo-8-methoxy-2-methyl-7-quinolinesulfonyl chloride, which is thetitle compound of Preparation 7, according to the procedures describedin Preparation 8 and Example 17, substituting benzylamine for4-chlorobenzylamine in the former procedure. Column chromatography(elution with 0.5-1% MeOH/CH₂Cl₂) followed by crystallization fromEtOAc/hexanes gives 0.197 g of the title compound as orange crystals.

Physical characteristics are as follows:

MP 113-114° C.

¹H NMR (300 MHz, CDCl₃) δ8.46, 7.94, 7.57, 7.22-7.08, 5.40, 4.15, 2.82ppm.

IR (mull) 3035, 3010, 1548, 1504, 1445, 1440, 1425, 1313, 1148, 1041,803, 734, 698, 681, 611 cm⁻¹.

MS (EI) m/z 362 (M+).

Anal found: C, 56.49; H, 4.25; N, 7.64.

EXAMPLE 285-Chloro-N-(4-chlorophenyl)-8-hydroxy-2-methyl-7-quinolinesulfonamide(Formula J-5 wherein R¹=Me, X¹=Cl, and R²=4-Cl—C₆H₄) Refer to Chart J

The title compound is prepared in two steps from5-bromo-8-methoxy-2-methyl-7-quinolinesulfonyl chloride, which is thetitle compound of Preparation 7, according to the procedures describedin Preparation 8 and Example 17, substituting 4-chloroaniline for4-chlorobenzylamine in the former procedure. Column chromatography(elution with 1% MeOH/CHCl₃) followed by crystallization fromEtOAc/hexane and rinsing with additional EtOAc gives 0.056 g of thetitle compound as a beige solid.

Physical characteristics are as follows:

MP 284-287° C. (decomposition).

¹H NMR (300 MHz, CDCl₃) δ8.20, 7.56, 7.41, 6.94-6.90, 2.56 ppm.

IR (mull) 1530, 1492, 1335, 1313, 1288, 1276, 1152, 1125, 1109, 1095,827, 742, 647, 635, 610 cm⁻¹.

MS (EI) m/z 382 (M+).

HRMS (EI) found 381.9940.

EXAMPLE 29 5-Chloro-8-hydroxy-2-methyl-N-octyl-7-quinolinesulfonamide(Formula J-5 wherein R¹=Me, X¹=Cl, and R²=(CH₂)₇CH₃) Refer to Chart J

The title compound is prepared in two steps from5-bromo-8-methoxy-2-methyl-7-quinolinesulfonyl chloride, which is thetitle compound of Preparation 7, according to the procedures describedin Preparation 8 and Example 17, substituting n-octylamine for4-chlorobenzylamine in the former procedure. Column chromatography(elution with 1-2% MeOH/CHCl₃) followed by crystallization fromEtOAc/hexane gives 0.045 g of the title compound as an orange solid.

Physical characteristics are as follows:

MP 85-100° C.

¹H NMR (300 MHz, CDCl₃) δ8.47, 7.93, 7.56, 5.22, 3.31, 2.82, 1.49-1.44,1.32-1.09, 0.84 ppm.

IR (mull) 3301, 1504, 1415, 1328, 1250, 1158, 1142, 1082, 948, 826, 725,688, 653, 634, 614 cm⁻¹.

MS (EI) m/z 384 (M+).

HRMS (EI) found 384.1270.

EXAMPLE 305-Chloro-N-[4-fluorophenyl)methyl]-8-hydroxy-2-methyl-7-quinolinesulfonamide(Formula J-5 wherein R¹=Me, X¹=Cl, and R²=CH₂-4-F—C₆H₄) Refer to Chart J

The title compound is prepared in two steps from5-bromo-8-methoxy-2-methyl-7-quinolinesulfonyl chloride, which is thetitle compound of Preparation 7, according to the procedures describedin Preparation 8 and Example 17, substituting 4-fluorobenzylamine for4-chlorobenzylamine in the former procedure. Column chromatography(elution with 0.5-1% MeOH/CH₂Cl₂) gives 0.135 g of the title compound asan orange foam.

Physical characteristics are as follows:

MP 143-146° C.

¹H NMR (300 MHz, CDCl₃) δ8.46, 7.92, 7.57, 7.18-7.15, 6.83, 5.40, 4.12,2.82 ppm.

IR (mull) 3318, 3270, 1510, 1425, 1352, 1330, 1319, 1250, 1221, 1152,1143, 835, 829, 634, 613 cm⁻¹.

MS (EI) m/z 380 (M+).

Anal found: C, 53.96; H, 4.03; N, 7.15.

EXAMPLE 315-Chloro-8-hydroxy-2-methyl-N-(1-naphthalenylmethyl)-7-quinolinesulfonamide(Formula J-5 wherein R¹=Me, X¹=Cl, and R²=CH₂-1-naphthyl) Refer to ChartJ

The title compound is prepared in two steps from5-bromo-8-methoxy-2-methyl-7-quinolinesulfonyl chloride, which is thetitle compound of Preparation 7, according to the procedures describedin Preparation 8 and Example 17, substituting 1-naphthalenemethylaminefor 4-chlorobenzylamine in the former procedure. Crystallization fromCH₂Cl₂/hexanes gives 0.127 g of the title compound as light browncrystals.

Physical characteristics are as follows:

MP 203-204° C.

¹H NMR (300 MHz, CDCl₃) δ8.39, 7.97, 7.80, 7.60, 7.53, 7.46, 7.36,7.29-7.17, 5.58, 4.63, 2.77 ppm.

IR (mull) 3265, 1440, 1350, 1329, 1155, 1146, 851, 836, 800, 783, 776,690, 640, 631, 608 cm⁻¹.

MS (EI) m/z 412 (M+).

HRMS (EI) found 412.0643.

EXAMPLE 325-Chloro-N-(cyclohexylmethyl)-8-hydroxy-2-methyl-7-quinolinesulfonamide(Formula J-5 wherein R¹=Me, X¹=Cl, and R²=CH₂-cyclohexyl) Refer to ChartJ

The title compound is prepared in two steps from5-bromo-8-methoxy-2-methyl-7-quinolinesulfonyl chloride, which is thetitle compound of Preparation 7, according to the procedures describedin Preparation 8 and Example 17, substituting cyclohexanemethylamine for4-chlorobenzylamine in the former procedure. Column chromatography(elution with MeOH/CH₂Cl₂) gives 0.257 g of the title compound as anorange foam.

Physical characteristics are as follows:

MP 113-115° C.

¹H NMR (300 MHz, CDCl₃) δ8.46, 7.95, 7.57, 5.12, 2.82, 2.74, 1.75-1.62,1.53-1.42, 1.29-1.08, 0.95-0.82 ppm.

IR (mull) 3284, 1503, 1413, 1344, 1338, 1329, 1249, 1159, 1143, 1061,948, 825, 725, 688, 610 cm⁻¹.

MS (EI) m/z 368 (M+).

Anal found: C, 55.62; H, 5.89; N, 7.46.

EXAMPLE 335-Chloro-N-[(3-chlorophenyl)methyl]-8-hydroxy-2-methyl-7-quinolinesulfonamide(Formula J-5 wherein R¹=Me, X¹=Cl, and R²=CH₂-3-C—C₆H₄) Refer to Chart J

The title compound is prepared in two steps from5-bromo-8-methoxy-2-methyl-7-quinolinesulfonyl chloride, which is thetitle compound of Preparation 7, according to the procedures describedin Preparation 8 and Example 17, substituting 3-chlorobenzylamine for4-chlorobenzylamine in the former procedure. Column chromatography(elution with 0.5-2% MeOH/CH₂Cl₂) gives 0.154 g of the title compound asa solid.

Physical characteristics are as follows:

MP 52-54° C.

¹H NMR (300 MHz, CDCl₃) δ8.43, 7.88, 7.56, 7.18-7.00, 5.48, 4.16, 2.80ppm.

IR (mull) 3311, 1600, 1503, 1433, 1329, 1251, 1158, 1143, 952, 829, 727,704, 687, 634, 617 cm⁻¹.

MS (EI) m/z 396 (M+).

Anal found: C, 51.27; H, 3.64; N, 7.00.

EXAMPLE 345-Chloro-8-hydroxy-2-methyl-N-(3-phenylpropyl)-7-quinolinesulfonamide(Formula J-5 wherein R¹=Me, X¹=Cl, and R²=CH₂CH₂CH₂Ph) Refer to Chart J

The title compound is prepared in two steps from5-bromo-8-methoxy-2-methyl-7-quinolinesulfonyl chloride, which is thetitle compound of Preparation 7, according to the procedures describedin Preparation 8 and Example 17, substituting 3-phenylpropylamine for4-chlorobenzylamine in the former procedure. Column chromatography(elution with 0.5% MeOH/0.005% NH₄OH/CH₂Cl₂ to 1% MeOH/0.01%NH₄OH/CH₂Cl₂) gives 0.343 g of the title compound as an orange foam.

Physical characteristics are as follows:

MP 131-134° C.

¹H NMR (300 MHz, CDCl₃) δ8.45, 7.93, 7.56, 7.24-7.10, 7.08, 5.11, 2.97,2.80, 2.63, 1.83 ppm.

IR (mull) 3231, 1416, 1350, 1329, 1253, 1154, 1151, 949, 827, 755, 727,701, 687, 634, 612 cm⁻¹.

MS (EI) m/z 390 (M+).

HRMS (EI) found 390.0798.

Anal found: C, 58.40; H, 5.00; N, 7.04.

EXAMPLE 355-Chloro-8-hydroxy-2-methyl-N-(2-phenoxyethyl)-7-quinolinesulfonamide(Formula J-5 wherein R¹=Me, X¹=Cl, and R²=CH₂CH₂OPh) Refer to Chart J

The title compound is prepared in two steps from5-bromo-8-methoxy-2-methyl-7-quinolinesulfonyl chloride, which is thetitle compound of Preparation 7, according to the procedures describedin Preparation 8 and Example 17, substituting 2-phenoxyethylamine for4-chlorobenzylamine in the former procedure. Column chromatography(elution with 0.5-1% MeOH/CH₂Cl₂) followed by crystallization fromCH₂Cl₂/hexanes gives 0.310 g of the title compound as orange crystals.

Physical characteristics are as follows:

MP 106-107° C.

¹H NMR (300 MHz, CDCl₃) δ8.38, 7.95, 7.51, 7.12, 6.82, 6.65, 5.72, 3.92,3.43, 2.77 ppm.

IR (mull) 2801, 1550, 1499, 1430, 1421, 1408, 1319, 1246, 1233, 1162,1150, 782, 758, 699, 689 cm⁻¹.

MS (EI) m/z 392 (M+).

HRMS (EI) found 392.0586.

EXAMPLE 365-Chloro-8-hydroxy-2-methyl-N-[3-(4-morpholinyl)propyl]-7-quinoline-sulfonamide(Formula J-5 wherein R¹=Me, X¹=Cl, and R²=CH₂CH₂CH₂-morpholine) Refer toChart J

The title compound is prepared in two steps from5-bromo-8-methoxy-2-methyl-7-quinolinesulfonyl chloride, which is thetitle compound of Preparation 7, according to the procedures describedin Preparation 8 and Example 17, substitutingN-(3-aminopropyl)morpholine for 4-chlorobenzylamine in the formerprocedure. Washing with CH₂Cl₂ gives 0.029 g of the title compound as abeige solid.

Physical characteristics are as follows:

MP 245-257° C.

¹H NMR (300 MHz, CDCl₃) δ8.50, 7,93, 7.58, 6.34, 4.30, 4.00, 3.57, 3.23,2.98-2.86, 2.85, 2.21 ppm.

MS (EI) m/z 399 (M+).

HRMS (EI) found 399.1021.

EXAMPLE 375-Chloro-8-hydroxy-N-[3-(1H-imidazol-1-yl)propyl]-2-methyl-7-quinolinesulfonamide(Formula J-5 wherein R¹=Me, X¹=Cl, and R²=CH₂CH₂CH₂-1-imidazole) Referto Chart J

The title compound is prepared in two steps from5-bromo-8-methoxy-2-methyl-7-quinolinesulfonyl chloride, which is thetitle compound of Preparation 7, according to the procedures describedin Preparation 8 and Example 17, substituting 1-(3-aminopropyl)imidazolefor 4-chlorobenzylamine in the former procedure. Washing with CH₂Cl₂gives 0.042 g of the title compound as a light brown solid.

Physical characteristics are as follows:

MP 194-196° C.

¹H NMR (300 MHz, DMSO-d₆) δ8.46, 7.81, 7.67, 7.09, 6.94, 4.11, 2.91,2.79, 1.95 ppm.

MS (EI) m/z 380 (M+).

HRMS (EI) found 380.0703.

EXAMPLE 38

5-Chloro-N-(diphenylmethyl)-8-hydroxy-2-methyl-7-quinolinesulfonamide(Formula J-5 wherein R¹=Me, X¹=Cl, and R²=CH(Ph)₂) Refer to Chart J

The title compound is prepared in two steps from5-bromo-8-methoxy-2-methyl-7-quinolinesulfonyl chloride, which is thetitle compound of Preparation 7, according to the procedures describedin Preparation 8 and Example 17, substituting 1,1-diphenylmethylaminefor 4-chlorobenzylamine in the former procedure. Column chromatography(elution with 0.5-1% MeOH/CH₂Cl₂) gives 0.156 g of the title compound asan orange foam.

Physical characteristics are as follows:

MP 115-119° C.

¹H NMR (300 MHz, CDCl₃) δ8.35, 7.73, 7.51, 7.11-6.98, 5.76, 5.58, 2.76ppm.

IR (mull) 3298, 1495, 1422, 1329, 1251, 1161, 1144, 952, 743, 727, 699,689, 652, 634, 614 cm⁻¹.

MS (EI) m/z 438 (M+).

HRMS (EI) found 438.0971.

EXAMPLE 39(R)-5-Chloro-8-hydroxy-2-methyl-N-(1-phenylethyl)-7-quinolinesulfonamide(Formula J-5 wherein R¹=Me, X¹=Cl, and R²=CH(Me)Ph) Refer to Chart J

The title compound is prepared in two steps from5-bromo-8-methoxy-2-methyl-7-quinolinesulfonyl chloride, which is thetitle compound of Preparation 7, according to the procedures describedin Preparation 8 and Example 17, substituting(R)-(+)-α-methylbenzylamine for 4-chlorobenzylamine in the formerprocedure. Column chromatography (elution with 0.5-1% MeOH/CH₂Cl₂)followed by precipitation of contaminant from CH₂Cl₂/hexanes gives 0.178g of the title compound as an orange foam.

Physical characteristics are as follows:

MP 84-88° C.

[α]_(D) (CHCl₃)=−49°.

¹H NMR (300 MHz, CDCl₃) δ8.35, 7.72, 7.51, 7.05, 6.93, 6.84, 5.41, 4.48,2.77, 1.47 ppm.

IR (mull) 3290, 1503, 1496, 1427, 1329, 1251, 1160, 1145, 1120, 952,727, 701, 689, 635, 623 cm⁻¹.

MS (EI) m/z 376 (M+).

EXAMPLE 40(S)-5-Chloro-8-hydroxy-2-methyl-N-(1-phenylethyl)-7-quinolinesulfonamide(Formula J-5 wherein R¹=Me, X¹=Cl, and R²=CH(Me)Ph) Refer to Chart J

The title compound is prepared in two steps from5-bromo-8-methoxy-2-methyl-7-quinolinesulfonyl chloride, which is thetitle compound of Preparation 7, according to the procedures describedin Preparation 8 and Example 17, substituting(S)-(−)-α-methylbenzylamine for 4-chlorobenzylamine in the formerprocedure. Column chromatography (elution with 0.5-1% MeOH/CH₂Cl₂) gives0.196 g of the title compound as an orange foam.

Physical characteristics are as follows:

MP 83-87° C.

[α]_(D) (CHCl₃)=+57°.

¹H NMR (300 MHz, CDCl₃) δ8.36, 7.73, 7.52, 7.05, 6.93, 6.85, 5.40, 4.49,2.78, 1.48 ppm.

IR (mull) 3299, 1503, 1496, 1423, 1329, 1251, 1160, 1146, 1085, 952,727, 701, 689, 635, 624 cm⁻¹.

MS (EI) m/z 376 (M+).

Anal found: C, 57.73; H, 4.63; N, 7.32.

Preparation 115-Chloro-8-[(1,1-dimethylethyl)dimethylsilyloxy]-7-iodoquinoline(Formula K-2 wherein X¹=Cl, X²=I, (R)₃=(Me₂)t-Bu) Refer to Chart K

A flame-dried, 50-mL, three-necked flask is charged with5-chloro-8-hydroxy-7-iodoquinoline (2.814 g), which is commerciallyavailable, t-butyldimethylchlorosilane (1.76 g), and 10 mL of DMF.Imidazole (1.66 g) is added, and the resulting mixture is stirred atroom temperature for 18 h. The reaction mixture is then quenched with 10mL of saturated aqueous NaHCO₃ and extracted with hexane three times.The combined organic layers are dried over MgSO₄, filtered andconcentrated to give 3.898 g of the title compound as a pale greensolid.

Physical characteristics are as follows:

MP 65-67° C.

¹H NMR (300 MHz, DMSO) δ8.94, 8.48, 8.07, 7.73, 1.08, 0.32 ppm.

IR (mull) 1570, 1485, 1408, 1356, 1255, 1250, 1244, 1097, 868, 838, 806,782, 678, 654, 640 cm⁻¹.

MS (FAB) m/z 420 (MH+).

Anal found: C, 43.05; H, 4.63; N, 3.31; Cl, 8.38.

EXAMPLE 41 5-Chloro-7-[(1,1-dimethylethyl)dimethylsilyl]-8-quinolinol(Formula K-3 wherein X¹=Cl, and (R)₃=(Me₂)t-Bu) Refer to Chart K

A flame-dried, 25-mL, two-necked flask is charged with the titlecompound of Preparation 11 (0.431 g) and 7 mL of THF. The resultingsolution is cooled to −78° C., and t-butyllithium (1.2 mL of 1.7 Msolution in pentane) is added dropwise over 2 min. The reaction mixtureis stirred for an additional 15 min at −78° C., the quenched by pouringinto 5 mL of half-saturated NH₄Cl (aq). The mixture is extracted with 50mL of EtOAc. The organic layer is separated, wahed with 15 mL ofsaturated NaHCO₃ (aq), dried over MgSO₄, filtered and concentrated togive 0.289 g of an off-white solid. Column chromatography (elution with2% EtOAc/hexane) yields 0.101 g of the title compound as a white solid.

Physical characteristics are as follows:

MP 107-108° C.

¹H NMR (300 MHz, DMSO) δ10.08, 8.94, 8.47, 7.74, 7.49, 0.88, 0.36 ppm.¹³C NMR (75 MHz, DMSO) δ158.0, 149.0, 138.2, 132.6, 132.2, 126.4, 123.7,118.4, 118.3, 26.9, 17.6, 4.8 ppm.

IR (mull) 3446, 1408, 1398, 1322, 1255, 1194, 949, 875, 836, 823, 810,786, 775, 718, 675 cm⁻¹.

MS (FAB) m/z 294 (MH+).

HRMS (FAB) found 294.1075.

EXAMPLE 42 5-Chloro-7-[(tris(1-methylethyl)silyl]-8-quinolinol (FormulaK-3 wherein X¹=Cl, and R=i-Pr) Refer to Chart K

The title compound is prepared in two steps from5-chloro-8-hydroxy-7-iodoquinoline, which is commercially available,according to the procedures described in Preparation 11 and Example 41,substituting triisopropylchlorosilane for t-butyl-dimethylchlorosilanein the former procedure. Column chromatography (elution th hexane) gives0.202 g of the title compound as a white solid.

Physical characteristics are as follows:

MP 107-108° C.

¹H NMR (300 MHz, CDCl₃) δ8.80, 8.76, 8.52, 7.57, 7.56, 1.58, 1.13 ppm.

IR (mull) 3430, 1485, 1399, 1321, 1256, 1196, 1181, 949, 882, 789, 719,681, 70, 644, 610 cm⁻¹.

MS (FAB) m/z 336 (MH+).

HRMS (FAB) found 392.2167.

Anal found: C, 64.68; H, 7.87; N, 4.04.

EXAMPLE 43 5-Chloro-7-[(1,1,-dimethylethyl)diphenylsilyl]-8-quinolinol(Formula K-3 wherein X¹=Cl, and (R)₃=Ph₂t-Bu) Refer to Chart K

The title compound is prepared in two steps from5-chloro-8-hydroxy-7-iodoquinoline, which is commercially available,according to the procedures described in Preparation 11 and Example 41,substituting t-butyldiphenylchlorosilane for t-butyldimethylchlorosilanein the former procedure. Column chromatography (elution with 1%EtOAc/hexane) gives 0.078 g of the title compound as a white foam.

Physical characteristics are as follows:

MP 133-139° C.

¹H NMR (300 MHz, CDCl₃) δ8.95, 8.83, 8.54, 7.62-7.56, 7.42-7.31, 1.26ppm.

IR (mull) 3317, 1485, 1428, 1398, 1339, 1198, 1110, 1103, 950, 786, 741,719, 699, 666, 605 cm⁻¹.

MS (FAB) m/z 418.

HRMS (FAB) found 418.1393.

Anal found: C, 71.73; H, 5.72; N, 3.29.

EXAMPLE 44 5-Chloro-7-(trimethylsilyl)-8-quinolinol (Formula K-3 whereinX¹=Cl, and R=Me) Refer to Chart K

The title compound is prepared in two steps from5-chloro-8-hydroxy-7-iodoquinoline, which is commercially available,according to the procedures described in Preparation 11 and Example 41,substituting trimethylchlorosilane for t-butyldimethylchlorosilane inthe former procedure. Column chromatography (elution with 0-1%EtOAc/hexane) gives 0.147 g of the title compound as a white solid.

Physical characteristics are as follows:

MP 109-111° C.

¹H NMR (300 MHz, CDCl₃) δ8.80, 8.55, 8.50, 7.55, 0.41 ppm.

IR (mull) 3414, 3377, 1398, 1334, 1243, 1202, 950, 883, 839, 788, 757,717, 628, 613, 605 cm⁻¹.

MS (FAB) m/z 252 (MH+).

HRMS (FAB) found 252.0597.

Anal found: C, 57.50; H, 5.54; N, 5.48.

EXAMPLE 45 5-Chloro-7-(dimethylphenylsilyl)-8-quinolinol (Formula K-3wherein X¹=Cl, and (R)₃=Me₂Ph) Refer to Chart K

The title compound is prepared in two steps from5-chloro-8-hydroxy-7-iodoquinoline, which is commercially available,according to the procedures described in Preparation 11 and Example 41,substituting triisopropylchlorosilane for t-butyl-dimethylchlorosilanein the former procedure. Column chromatography (elution with 1%EtOAc/hexane) gives 0.065 g of the title compound as a white solid.

Physical characteristics are as follows:

MP 101-103° C.

¹H NMR (300 MHz, CDCl₃) δ8.80, 8.61, 8.49, 7.65-7.62, 7.55, 7.45,7.39-7.37. 0.70ppm.

IR (mull) 3323, 1427, 1396, 1324, 1249, 1188, 949, 879, 837, 819, 783,719, 700, 696, 665 cm⁻¹.

MS (FAB) m/z 314 (MH+).

HRMS (FAB) found 314.0763.

Anal found: C, 64.85; H, 5.24; N, 4.46.

EXAMPLE 46N-[(4-Chlorophenyl)methyl]-4,8-dihydroxy-2-trifluoromethyl-7-quinolinecarboxamide

To a solution of the title compound of Preparation 20 (0.273 g) in 10 mLDMF is added 4-chlorobenzylamine (0.134 mL), EDC-HCl (0.210 g) andHOBt-H2O (0.149 g). The mixture is allowed to stir for 3 days, thenpoured into 50 mL of ice-water. The resulting precipitate is collectedand dried. The crude product is recrystallized from EtOAc/hexanes toyield 0.245 g of the title compound as a tan solid.

Physical characteristics are as follows:

MP 135-140° C. (dec).

¹H NMR (DMSO) δ13.83, 12.46, 9.60, 8.02, 7.61, 7.39, 7.20, 4.54.

IR (mull) 1924, 1905, 1644, 1629, 1600, 1585, 1558, 1527, 1428, 1338,1270, 1254, 1189, 1174, 1137 cm⁻¹.

MS (El) m/z 396 (M+), 398, 396, 256, 255, 229, 140, 127, 126, 125, 89.

Anal. found: C, 54.42; H, 3.17; N, 6.85; Cl, 8.66.

Preparation 12 2-[2-(4-Methoxyphenyl)ethenyl]-8-quinolinol

A mixture of 8-hydroxyquinaldine (9.93 g) and p-anisaldehyde (20 mL) isheated at 180° C. overnight. The reaction is then cooled to roomtemperature and vacuum distilled. Once the majority of thep-anisaldehyde is distilled off (below 100° C. ), the residue remainingin the flask is taken up in hot 95% EtOH. Any undissolved material isfiltered off. H₂O is added to the EtOH filtrate and the product isobtained as a yellow solid (3.42 g).

Physical characteristics are as follows:

MP 108-110° C.

¹H NMR (300 MHz, CDCl₃) δ8.15, 7.69, 7.59, 7.39, 7.30, 7.27, 7.18, 6.95,3.86.

¹³C NMR (75 MHz, DMSO-d₆) δ160.21, 154.25, 153.30, 138.60, 136.84,134.58, 129.56, 129.10, 127.97, 127.24, 126.10, 121.25, 118.02, 114.84,111.59, 55.66.

IR (mull) 3420, 2290, 2039, 1943, 1603, 1598, 1558, 1513, 1505, 1273,1255, 1240.

MS (OAMS) 278.2 (M+).

Anal. found: C, 77.48; H, 5.37; N, 5.14.

Preparation 13 2-(2-Phenylethenyl)-8-quinolinol

A mixture of 8-hydroxyquinaldine (10.02 g) and benzaldehyde (16.8 mL) isheated at reflux overnight. The reaction is cooled to room temperatureand vacuum distilled. After the excess benzaldehyde has distilled off,the residue remaining in the flask is dissolved in hot 95% EtOH. Anyundissolved material is filtered off. The EtOH filtrate is cooled slowlyto give the product as light yellow crystals (5.17 g).

Physical characteristics are as follows:

MP 70-72° C.

¹H NMR (300 MHz, CD₃OD) δ8.17, 7.82, 7.77, 7.68, 7.66, 7.44, 7.39, 7.36,7.31, 7.08.

¹³C NMR (75 MHz, CD₃OD) 67 154.09, 152.60, 138.23, 136.63, 136.18,134.19, 128.41, 128.23, 127.97, 127.92, 126.89, 126.74, 119.54, 117.53,110.55.

IR (mull) 1949, 1915, 1903, 1444, 1337, 1260, 1089, 960, 956, 836, 756,747, 724, 697, 689 cm⁻¹.

MS (OAMS) 248.2 (M+).

Anal. found: C, 82.38; H, 5.28; N, 5.68.

EXAMPLE 47N-[(4-Chlorophenyl)methyl]-8-hydroxy-2-[2-(4-methoxyphenyl)ethenyl]-7-quinolinecarboxamide

The title compound of Preparation 14 (0.25 g) and 4-chlorobenzylamine(0.10 mL) are dissolved in 10 mL DMF. EDC.HCl (0.16 g) and HOBt.H₂O(0.11 g) is added in one portion and the reaction is allowed to stir atroom temperature overnight. The reaction is then poured into 50 mLice/water. The resulting orange solid is filtered and chromatographed onsilica gel (eluent 2% MeOH:CH₂Cl₂). The product-containing fractions areevaporated under reduced pressure to give the product as a light brownsolid (0.029 g).

Physical characteristics are as follows:

MP 200-201° C.

¹H NMR (300 MHz, DMSO-d₆) δ9.28, 8.27, 7.95, 7.88, 7.66, 7.40, 7.37,7.33, 7.00, 4.56, 3.78.

¹³C NMR (75 MHz, DMSO-d₆) δ168.46, 160.33, 156.50, 155.32, 139.29,138.64, 136.80, 134.97, 131.96, 129.83, 129.71, 129.37, 129.23, 128.82,126.11, 124.85, 122.46, 117.37, 114.86, 113.31, 60.93, 55.70.

IR (mull) 2428, 2287, 2050, 2016, 1951, 1640, 1600, 1535, 1514, 1439,1266, 1237, 1173, 1107, 846 cm⁻¹.

MS (OAMS) 322.2 (M+).

HRMS (EI) found 444.1247.

Anal. found: C, 67.36; H, 4.70; N, 6.11.

Preparation 148-Hydroxy-2-[2-(4-methoxyphenyl)ethenyl]-7-quinolinecarboxylic acid

The title compound of Preparation 12 (3.00 g) is mixed with K₂CO₃ (4.51g) and loaded into a small stainless steel bomb. The bomb is flushed 3×with 100 psi CO₂ and then pressurized to the pressure of the CO₂ tank.The bomb is heated at 170° C. for 7 days, maintaining a final pressureof approximately 1200 psi. The bomb is de-pressurized and cooled to roomtemperature. The residue is dissolved in a minimal amount of warm water.The aqueous mixture is acidified with concentrated HCl. The materialwhich precipitates at pH 7 (starting material) is filtered and thefiltrate is further acidified to pH 4. The product is obtained as ayellow/orange solid which is further purified by trituration in iPrOH(0.74 g).

Physical characteristics are as follows:

MP 217-219° C.

¹H NMR (300 MHz, DMSO-d₆) δ8.51, 8.17, 7.96, 7.84, 7.67, 7.58, 7.28,7.03, 3.80.

¹³C NMR (75 MHz, DMSO-d₆) δ171.49, 161.15, 159.55, 153.84, 140.30,138.81, 135.38, 131.05, 129.84, 128.68, 127.56, 122.21, 121.57, 115.41,115.05, 112.74, 55.79.

IR (mull) 2035, 1932, 1628, 1596, 1573, 1515, 1428, 1338, 1328, 1315,1289, 1269, 1250, 1176, 836 cm⁻¹.

MS (El) m/z 321 (M+), 321, 303, 302, 277, 276, 275, 274, 260, 232, 151.

HRMS (EI) found 321.1001.

Anal. found: C, 66.11; H, 4.77; N, 4.02.

Preparation 15 8-Hydroxy-2-(2-phenylethenyl)-7-quinolinecarboxylic acid

The title compound of Preparation 13 (3.50 g) and K₂CO₃ (6.00 g) aremixed and placed in a stainless steel bomb. The bomb is flushed 2× with100 psi CO₂ and then pressurized to approximately 800 psi CO₂. Thereaction us heated at 170° C. for 7 days, maintaining a pressure of 1300psi. The bomb is then cooled to room temperature and the pressurereleased. The residue is dissolved in 900 mL H₂O warm water. The aqueousmixture is acidified to pH 4 with concentrated HCl to give a brightorange solid. The solid is then triturated in iPrOH to give the product(2.21 g).

Physical characteristics are as follows:

MP 208-210° C.

¹H NMR (300 MHz, DMSO-d₆) δ8.43, 8.10, 7.94, 7.82, 7.72, 7.62, 7.43,7.31.

¹³C NMR (75 MHz, DMSO-d₆) δ171.87, 160.31, 154.06, 138.74, 137.54,136.76, 136.36, 131.34, 129.67, 129.42, 127.90, 127.06, 126.74, 122.10,116.00, 111.82.

IR (mull) 1945, 1904, 1722, 1687, 1617, 1596, 1579, 1563, 1489, 1435,1419, 1410, 1351, 1304, 1208 cm⁻¹.

MS (El) m/z 291 (M+) 291, 291, 273, 272, 248, 247, 246, 245, 244, 217,216.

HRMS (EI) found 291.0910.

% Water (KF): 1.42.

Anal. found: C, 72.28; H, 4.71; N, 4.76.

EXAMPLE 48N-Heptyl-8-hydroxy-2-[2-(4-methoxyphenyl)ethenyl]-7-quinolinecarboxamide

The title compound of Preparation 14 (0.16 g) and heptylamine (0.08 mL)are dissolved in 6 mL DMF. EDC.HCl (0.10 g) and HOBt.H₂O (0.07 g) areadded in one portion and the reaction is stirred at room temperature for3 days. The reaction is poured into 50 mL ice/H₂O. The aqueous solutionis extracted 3× with EtOAc. The organic layers are combined, dried overMgSO₄, evaporated, and adsorbed onto silica. The product is purified bysilica gel chromatography (eluent 2% MeOH:CH₂Cl₂). The productcontaining fractions are evaporated and the resulting residue iscrystallized with Et₂O/hexanes to give the product as a tan solid (0.019g).

Physical characteristics are as follows:

MP 115-116° C.

¹H NMR (300 MHz, DMSO-d₆) δ8.77, 8.26, 7.91, 7.87, 7.66, 7.33, 7.31,7.00, 3.79, 3.33, 1.57, 1.28, 0.84.

MS (El) i/z 418 (M+), 418, 305, 304, 302, 278, 277, 276, 275, 260, 152.

HRMS (FAB) found 419.2335.

Anal. found: C, 72.67; H, 6.87; N, 6.45.

EXAMPLE 49 N-Heptyl-8-hydroxy-2-(2-phenylethenyl)-7-quinolinecarboxamide

The title compound of Preparation 15 (0.31 g) and heptylamine (0.17 mL)are dissolved in 12 mL DMF. EDC.HCl (0.22 g) and HOBt.H₂O (0.16 g) areadded and the reaction is stirred at room temperature for 3 days. Thereaction is then poured into 50 mL ice/H₂O amd the aqueous solution isextracted 3× with EtOAc. The EtOAc extracts are combined, dried overMgSO₄, evaporated, and the residue is adsorbed onto silica. The productis purified by chromatography (eluent 1% MeOH:CH₂Cl₂). Theproduct-containing fractions are evaporated under reduced pressure andthe residue crystallized with Et₂O/hexanes to give the product as alight brown solid (0.10 g).

Physical characteristics are as follows:

MP 113-115° C.

¹H NMR (300 MHz, DMSO-d₆) δ8.78, 8.26, 7.94, 7.89, 7.90, 7.69, 7.47,7.40, 7.33, 3.33, 1.54, 1.24, 0.81.

R (mull) 3387, 2281, 1960, 1944, 1927, 1643, 1600, 1547, 1504, 1441,1152, 989, 751, 690, 622 cm⁻¹.

MS (OAMS) 389.2 (M+).

HRMS (EI) found: 388.2127.

Anal. found: C, 76.75; H, 7.38; N, 7.28.

EXAMPLE 508-Hydroxy-N-(2-hydroxy-2-phenylethyl)-2-(2-phenylethenyl)-7-quinolinecarboxamide

The title compound of Preparation 15 (0.33 g) and2-amino-1-phenylethanol (0.18 g) are dissolved in 10 mL DMF. EDC.HCl(0.24 g) and HOBt.H₂O (0.17 g) are added in one portion and the reactionis allowed to stir at room temperature for 4 days. The reaction ispoured into 50 mL ice/H₂O and the resulting solid is filtered. The solidis dissolved in EtOAc. To remove unreacted starting material, hexanesare added and the solid is filtered. The product is obtained as a foamyorange solid upon evaporation of the filtrate (0.17 g).

Physical characteristics are as follows:

MP 83-86° C.

¹H NMR (300 MHz, DMSO-d₆) δ8.92, 8.31, 8.10, 7.96, 7.89, 7.72, 7.49,7.34, 5.68, 4.80, 3.65.

¹³C NMR (75 MHz, DMSO-d₆) δ167.42, 155.51, 154.83, 144.02, 139.21,136.93, 136.83, 135.30, 129.81, 129.39, 129.22, 128.58, 128.33, 127.71,127.62, 126.44, 125.79, 122.84, 117.43, 113.84, 71.45, 60.67, 47.73.

IR (mull) 3376, 3059, 3028, 1950, 1640, 1600, 1545, 1506, 1495, 1436,1418, 1350, 1329, 751, 699 cm⁻¹.

MS (FAB) m/z 411 (MH+), 487, 413, 412, 411, 410, 304, 303, 275, 274,248.

HRMS (FAB) found 411.1710.

Anal. found: C, 75.00; H, 5.40; N, 7.23.

EXAMPLE 51N-[(4-Chlorophenyl)methyl]-8-hydroxy-2-(2-phenylethenyl)-7-quinolinecarboxamide

The title compound of Preparation 15 (0.25 g) and 4-chlorobenzylamine(0.12 mL) are dissolved in 10 mL DMF. EDC.HCl (0.19 g) and HOBt.H₂O(0.13 g) are added and the reaction is stirred at room temperature for 3days. The reaction is poured into 50 mL ice/H₂O and the resulting solidis filtered and dried. The solid is recrystallized from EtOAc to givethe product as a yellow solid (0.12 g).

Physical characteristics are as follows:

MP 192-194° C.

¹H NMR (300 MHz, DMSO-d₆) δ9.29, 8.31, 8.01, 7.92, 7.71, 7.49, 7.39,4.57.

¹³C NMR (75 MHz, DMSO-d₆) δ168.44, 156.56, 154.97, 139.35, 138.62,136.89, 136.77, 135.16, 131.97, 130.01, 129.72, 129.38, 129.22, 128.82,128.53, 127.71, 125.10, 122.68, 117.43, 113.38, 42.50.

IR (mull) 3383, 2285, 1946, 1930, 1641, 1603, 1536, 1506, 1435, 1425,1345, 1106, 963, 750, 612 cm⁻¹.

MS (FAB) m/z 415 (MH+), 418, 417, 416, 415, 414, 275, 274, 247, 125,123.

HRMS (FAB) found 415.1206.

Anal. found: C, 70.89; H, 4.72; N, 6.52.

EXAMPLE 528-Hydroxy-2-(2-phenylethenyl)-N-[2-(phenylthio)ethyl]-7-quinolinecarboxamide

The title compound of Preparation 15 (0.23 g) and CDI (0.14 g) aredissolved in 15 mL DMF and stirred at room temperature overnight.2-Aminoethyl phenylsulfide (0.14 g) is added and the reaction is allowedto stir for 5 days. The reaction is then poured into 50 mL ice/H₂O andstirred for 2 hours. The resulting light yellow solid is filtered anddried. The solid is recrystallized from EtOAc/hexanes to give theproduct as a light brown solid (0.18 g).

Physical characteristics are as follows:

MP 131-132° C.

¹H NMR (300 MHz, DMSO-d₆) δ9.00, 8.30, 8.00, 7.92, 7.87, 7.72, 7.49,7.40, 7.33, 7.18, 3.58, 3.21. ¹³C NMR (75 MHz, DMSO-d₆) δ168.47, 156.63,154.97, 139.38, 136.88, 136.77, 135.96, 135.14, 130.02, 129.60, 129.39,129.22, 128.68, 128.57, 127.72, 126.31, 125.06, 122.65, 117.37, 113.20,31.81.

IR (mull) 3378, 2294, 1943, 1932, 1645, 1603, 1536, 1505, 1435, 1424,1144, 747, 731, 683, 622 cm⁻¹.

MS (OAMS) 427.3 (MH+).

HRMS (EI) found 426.1390.

Anal. found: C, 72.48; H, 5.22; N, 6.55.

EXAMPLE 538-Hydroxy-N-(2-hydroxy-2-phenylethyl)-2-[2-(4-methoxyphenyl)-ethenyl]-7-quinolinecarboxamide

The title compound of Preparation 14 (0.57 g) and2-amino-1-phenylethanol 0.26 g) are dissolved in 15 mL DMF. EDC.HCl(0.37 g) and HOBt.H₂O (0.25 g) are added and the reaction is stirred atroom temperature for 4 days. The reaction is poured into 100 mL ice/H₂O.The resulting solid is filtered, dried, and recrystallized fromEtOAc/hexanes to give the product as an orange solid (0.26 g).

Physical characteristics are as follows:

MP 203-205° C.

¹H NMR (300 MHz, DMSO-d₆) δ8.92, 8.27, 8.04, 7.93, 7.84, 7.66, 7.42,7.34, 7.25, 7.01, 4.81, 3.79, 3.64, 3.42.

IR (mull) 3365, 2068, 1929, 1638, 1620, 1601, 1555, 1531, 1514, 1438,1422, 1269, 1236, 1176, 828 cm⁻¹.

MS (FAB) m/z 441 (MH+), 883, 882, 442, 441, 440, 333, 305, 304, 123,121.

HRMS (FAB) found 441.1818.

Anal. found: C, 73.05; H, 5.39; N, 6.32.

EXAMPLE 548-Hydroxy-2-[2-(4-methoxyphenyl)ethenyl]-N-[2-(phenylthio)ethyl]-7-quinolinecarboxamide

The title compound of Preparation 14 (0.57 g) and 2-aminoethylphenylsulfide (0.30 g) are dissolved in 15 mL DMF. EDC.HCl (0.36 g) andHOBt.H₂O (0.26 g) are added and the reaction is stirred at roomtemperature for 4 days. The reaction is poured into 100 mL ice/H₂O. Theresulting solid is filtered, dried, and recrystallized fromEtOAc/hexanes. The product is obtained as an orange solid (0.29 g).

Physical characteristics are as follows:

MP 163-165° C.

¹H NMR (300 MHz, DMSO-d₆) δ9.00, 8.27, 7.95, 7.87, 7.84, 7.66, 7.42,7.34, 7.18, 7.00, 3.79, 3.57, 3.20.

¹³C NMR (75 MHz, DMSO-d₆) δ168.48, 160.33, 156.56, 155.31, 139.35,136.72, 135.98, 134.92, 129.83, 129.58, 129.38, 129.21, 128.68, 126.29,126.19, 124.84, 122.39, 117.29, 114.84, 113.18, 55.67, 31.84.

IR (mull) 2425, 2349, 2294, 2042, 1942, 1644, 1599, 1535, 1513, 1442,1258, 1245, 1176, 826, 739 cm⁻¹.

MS (El) m/z 456 (M+), 456, 333, 320, 305, 304, 303, 302, 275, 260, 232.

HRMS (EI) found 456.1489.

Anal. found: C, 69.99; H, 5.36; N, 5.95.

Preparation 16 8-Methoxy-2-(trifluoromethyl)-4-quinolinol

A mixture of o-anisidine (28 mL), ethyl trifluoroacetoacetate (36 mL),and 12 drops 6N HCl is stirred overnight to form the enamine. The waterformed during the reaction is removed by evaporation under reducedpressure. The residue is then poured into 60 mL diphenyl ether in aflask equipped with a Dean-Stark trap and condenser. The reaction isheated at 250° C. for 3 hours, cooled, and the resulting solid isfiltered. The solid is rinsed thoroughly with hexanes and dried (18.77g).

Physical characteristics are as follows:

MP 151-153° C.

¹H NMR (300 MHz, CDCl₃) δ7.90, 7.37, 7.15, 6.83, 4.05.

¹³C NMR (75 MHz, DMSO-d₆) δ163.20, 155.74, 146.63, 146.21, 140.56,128.02, 122.79, 113.71, 110.36, 100.89, 56.17.

IR (mull) 2498, 2471, 1549, 1527, 1481, 1438, 1415, 1288, 1270, 1202,1182, 1150.

MS (OAMS) 244.1 (MH+).

Anal. found: C, 54.16; H, 3.36; N, 5.77.

Preparation 17 4-Chloro-8-methoxy-2-(trifluoromethyl)quinoline

4-Hydroxy-8-methoxy-2-trifluoromethylquinoline (18.77 g) is dissolved in450 mL 8:1 CH₂Cl₂:DMF. POCl₃ (50 mL) is added dropwise and the reactionis allowed to stir overnight. The reaction is then poured into 500 mLice/H₂O and the aqueous is extracted 2× with CH₂Cl₂. The organicportions are combined, washed 1× with brine, dried over MgSO₄, andevaporated. The resulting oil crystallizes upon standing. The solid isrecrystallized from 95% EtOH. A second crop of crystals could beobtained by concentrating down the EtOH filtrate. The total yield ofproduct is 15.36 g.

Physical characteristics are as follows:

¹H NMR (300 MHz, DMSO-d₆) δ8.26, 7.81, 7.44, 4.02.

Preparation 18 8-Methoxy-2-(trifluoromethyl)quinoline

To a solution of 4-chloro-8-methoxy-2-trifluoromethylquinoline (0.57 g)in 5 mL absolute EtOH is added 10% Pd/C (125 mg) and NEt₃ (0.3 mL). Thereaction is hydrogenated under atmospheric pressure for 0.75 h. Thereaction is then filtered over Celite and the filtrate is evaporated.The residue is taken up in Et₂O and the triethylamine hydrochloride saltis filtered. The desired product is obtained as a light yellow solid byevaporation of the Et₂O filtrate (0.38 g).

Physical characteristics are as follows:

MP 88-89° C.

¹H NMR (300 MHz, DMSO-d₆) δ8.63, 7.95, 7.68, 7.63, 7.32, 3.99.

¹³C NMR (75 MHz, DMSO-d₆) δ155.71, 145.50, 139.35, 138.83, 130.37,130.02, 119.81, 117.86, 117.83, 110.20, 56.28.

IR (mull) 2354, 2151, 2030, 1996, 1934, 1507, 1442, 1341, 1319, 1287,1275, 1210.

MS (OAMS) 228.2 (MH+).

Anal. found: C, 57.85; H, 3.34; N, 6.00.

Preparation 19 8-Hydroxy-2-(trifluoromethyl)-7-quinolinecarboxylic acid

8-Hydroxy-2-trifluoromethylquinoline (3.2 g) and K₂CO₃ (6.22 g) areplaced in a stainless steel bomb. The bomb is pressurized slightly withCO₂ and flushed 3×, then pressurized to approximately 800 psi CO₂. Thebomb is heated to 170° C., reaching a final pressure of approximately1200 psi. This temperature and pressure are maintained for 7 days afterwhich time the bomb is cooled and the pressure released. The solidresidue is dissolved in a minimal amount of warm water. Any undissolvedmaterial is filtered and the aqueous filtrate is acidified to pH 4 withconc. HCl. The resulting tan solid is filtered and dried. The product isrecrystallized with Et₂O to give a light tan solid (1.87 g).

Physical characteristics are as follows:

MP 209-211° C.

¹H NMR (300 MHz, DMSO-d₆) δ8.66, 8.06, 7.98, 7.54.

¹³C NMR (75 MHz, DMSO-d₆) δ172.69, 160.38, 146.32, 139.54, 138.44,133.29, 128.55, 123.74, 120.09, 120.01, 117.96, 111.33.

IR (mull) 3076, 3044, 1988, 1928, 1654, 1623, 1434, 1330, 1264, 1211,1188, 1150.

MS (El) m/z 257 (M+), 257, 240, 239.

Anal. found: C, 51.78; H, 2.67; N, 5.46.

EXAMPLE 55N-[(4-Chlorophenyl)methyl]-8-hydroxy-2-(trifluoromethyl)-7-quinolinecarboxamide

The title compound of Preparation 19 (0.52 g) and 4-chlorobenzylamine(0.26 mL) are dissolved in 10 mL DMF at room temperature. EDC.HCl (0.40g) and HOBt.H₂O (0.29 g) are added in one portion and the reaction isstirred at room temperature overnight. The reaction is then poured into50 mL ice/H₂O and the resulting yellow solid is filtered and dried. Theproduct is purified by silica gel chromatography (eluent 2% MeOH:CH₂Cl₂followed by 5% MeOH:CH₂Cl₂). The appropriate fractions are rotovapped togive an oily residue which crystallizes upon addition of CHCl₃. Theproduct is obtained as a tan solid (0.49 g).

Physical characteristics are as follows:

MP 92-94° C.

¹H NMR (300 MHz, DMSO-d₆) δ13.98, 9.63, 8.63, 8.15, 8.04, 7.57, 7.39,4.56.

IR (mull) 3363, 1996, 1613, 1600, 1552, 1493, 1440, 1352, 1342, 1326,1186, 1130.

MS (El) m/z 380 (M+), 240, 214, 213.

Anal. found: C, 57.37; H, 3.47; N, 7.13.

EXAMPLE 56 N-Heptyl-8-hydroxy-2-(trifluoromethyl)-7-quinolinecarboxamide

The title compound of Preparation 19 (0.35 g) and heptylamine (0.22 mL)are dissolved in 10 mL DMF. EDC.HCl (0.28 g) and HOBt.H₂O (0.21 g) areadded and the reaction is stirred at room temperature overnight. Thereaction is poured into 50 mL ice/H₂O and the aqueous is extracted 2×with EtOAc. The combined EtOAc layers are dried over MgSO₄, filtered,and evaporated to give an orange oil. The residue is adsorbed ontosilica and chromatographed eluting with 2% MeOH:CH₂Cl₂ followed by 5%MeOH:CH₂C₂. The fractions containing desired product are evaporatedunder reduced pressure to give a pale yellow oil which crystallizes withCH₂Cl₂/hexanes (0.15 g).

Physical characteristics are as follows:

MP 97-99° C.

¹H NMR (300 MHz, DMSO-d₆) δ14.4, 9.06, 8.61, 8.11, 8.02, 7.53, 3.34,1.56, 1.25, 0.82.

¹³C NMR (75 MHz, DMSO-d₆) δ169.65, 159.52, 146.12, 145.66, 139.32,138.98, 132.23, 126.60, 119.52, 117.14, 112.67, 31.68, 31.58, 29.19,28.86, 26.89, 22.51, 14.38.

IR (mull) 3371, 1938, 1613, 1602, 1558, 1440, 1358, 1329, 1280, 1211,1190, 1140.

MS (OAMS) 355.1 (MH+).

Anal. found: C, 60.68; H, 5.96; N, 7.80.

PREPARATION 20 4,8-Dihydroxy-2-(trifluoromethyl)-7-quinolinecarboxylicacid

2-Trifluoromethyl-4,8-dihydroxyquinoline (6.0 g) and K₂CO₃ (11.0 g) aremixed in a stainless steel bomb. The bomb is flushed and evacuated 3×with 100 psi CO₂. The reaction vessel is then pressurized to 800 psi CO₂and heated to 170° C., reaching a final pressure of 1200 psi. The bombremains at this temperature and pressure for 7 days. The reaction vesselis cooled to room temperature, the pressure is released, and thereaction mixture is dissolved in 300 mL hot water. Any undissolvedmaterial is filtered and the filtrate is acidified with conc. HCl. Aprecipitate at pH 7 is collected (starting material). The filtrate isfurther acidified to pH 4 where a tan solid is collected (startingmaterial+desired product). Since most of the solid collected is startingmaterial, this material is reacted in the bomb for 7 more days. The sameworkup as before is done, with the only precipitate collected at pH 4.5.The desired product is filtered, dried, and recrystallized very slowlywith EtOAc/hexanes (0.41 g).

Physical characteristics are as follows:

MP 232-234° C.

¹H NMR (300 MHz, DMSO-d₆) δ7.88, 7.62, 7.22.

MS (EI) m/z 273 (M+), 256, 255, 243, 229, 228, 227, 199, 179, 151.

HRMS (EI) found 273.0252.

Anal. found C, 46.37; H, 3.11; N, 4.69.

Preparation 21 2-[2-(2-furyl)ethenyl]-8-quinolinol

A mixture of 8-hydroxyquinaldine (5.09 g) and 2-furaldehyde (8.0 mL) areheated at reflux overnight. The reaction is cooled to room temperature.The residue is taken up in acetone and adsorbed onto silica. A silicagel column eluting with 100% CH₂Cl₂ is run and the product-containingfractions evaporated under reduced pressure to give an orange/yellowoil. The product is crystallized with EtOH/H₂O, filtered, washedthoroughly with water, and dried (1.18 g).

Physical characteristics are as follows:

MP 80-82° C.

¹H NMR (300 MHz, DMSO-d₆) δ9.55, 8.24, 7.97, 7.78, 7.71, 7.33, 7.19,7.05, 6.70, 6.61.

IR (mull) 3340, 1555, 1508, 1336, 1259, 1229, 1205, 1184, 1158, 1150,1007, 969, 926, 835, 732 cm⁻¹.

MS (electrospray) 238.1 (MH+).

Anal. found: C, 75.74; H, 4.68; N, 5.85.

Preparation 22 2-[2-(2-furyl)ethenyl]-8-hydroxy-7-quinolinecarboxylicacid

The title compound of Preparation 21 (2.85 g) and K₂CO₃ (5.11 g) aremixed in a stainless steel bomb. The bomb is pressurized with 100 psiCO₂ and flushed 3×. The reaction vessel is then pressurized to 800 psiand heated to 175° C., reaching a final pressure of 1200 psi CO₂ whereit remained for 7 days. The bomb is cooled to room temperature andde-pressurized. The reaction residue is taken up in 900 mL hot water.Any undissolved material is filtered. The filtrate is acidified to pH 4with c.HCl and the resulting orange solid filtered and dried. The solidis then recrystallized with iPrOH to give the product as an orange solid(0.37 g).

Physical characteristics are as follows:

MP 190-192° C.

¹H NMR (300 MHz, DMSO-d₆) δ8.40, 8.02, 7.84, 7.81, 7.35, 7.28, 6.83,6.64.

IR (mull) 1691, 1651, 1608, 1551, 1482, 1342, 1307, 1287, 1238, 1205,1019, 960, 883, 747, 729 cm⁻¹.

HRMS (EI) found 281.0678.

Anal. found: C, 67.25; H, 4.04; N, 4.79.

EXAMPLE 57N-[(4-Chlorophenyl)methyl]-2-[2-(2-furyl)ethenyl]-8-hydroxy-7-quinolinecarboxamide

The title compound of Preparation 22 (0.26 g) and 4-chlorobenzylamine(0.13 mL) are dissolved in 10 mL DMF. EDC.HCl (0.19 g), and HOBt.H₂O(0.14 g) are added in one portion and the reaction stirred at roomtemperature over 3 days. The reaction is then poured into 75 mL ice/H₂O.The resulting solid is filtered, taken up in EtOAc, and adsorbed ontosilica. A column eluting with 2% MeOH/CH₂Cl₂ is run and theproduct-containing fractions are evaporated under reduced pressure togive an oil. The product residue is crystallized with CH₂Cl₂/hexanes.The product is filtered and dried on the vacuum pump (0.19 g).

Physical characteristics are as follows:

MP 165-167° C.

¹H NMR (300 MHz, DMSO-d₆) δ9.60, 8.28, 7.90, 7.89, 7.84, 7.79, 7.40,7.38, 7.21, 6.76, 6.61, 4.56.

IR (mull) 3382, 1642, 1602, 1536, 1483, 1439, 1433, 1342, 1135, 1106,1017, 961, 846, 737, 728 cm−1.

HRMS (EI) calcd 404.0913.

Anal. found (av): C, 60.98; H, 3.90; N, 6.13; Cl, 7.56.

EXAMPLE 58 N-[(4-Chlorophenyl)methyl]-8-hydroxy-7-quinoline-N-oxidecarboxamide

Hydrogen peroxide (0.2 mL of a 30% solution) is added to a solution ofthe title compound of Example 1 (0.100 g) in acetic acid (2.0 mL) andthe solution is refluxed for 2 h. The solution is poured over ice andsaturated sodium bicarbonate is slowly added until the pH of the mixtureis basic. The mixture is extracted with chloroform and the organic layeris concentrated to give 0.128 g yellow solid. Column chromatography onsilica gel (50 g) using 100% chloroform then 1% and 2%methanol/chloroform as eluant yields 35 mg (33%) of the desired productas a yellow solid. An analytical sample is crystallized from ethylacetate/hexane to give the title compound as an orange solid.

Physical characteristics are as follows:

MP 178-183° C.

IR (mull) 3370, 1649, 1612, 1531, 1492, 1425, 1403, 1394, 1269, 1091,1049, 830, 807, 693, 608 cm⁻¹.

MS (FAB) m/z 329 (MH+), 331, 330, 329, 315, 314, 313, 188, 184, 172,125.

HRMS (FAB) 329.0699.

Preparation 23 5-Chloro-8-hydroxy-2-methyl-7-quinolinesulfonyl flouride(Formula P-2) Refer to Chart P

A solution of 5-chloro-8-hydroxy-2-methylquinoline (9.2 g) in 55 mL offluorosulfonic acid is stirred at 120° C. for 18 h in a tightlystoppered flask. The mixture is then cooled to −78° C. and poured ontoan intimate mixture of 250 mL of crushed ice and 250 mL of powdered dryice. The mixture is allowed to warm to 25° C., and then diluted withdistilled water until further addition causes no additional solid toprecipitate (ca. 100 mL). The mixture is filtered, and the solidobtained is washed with four 50 mL-portions of 0° C. distilled water andthen dried in a stream of air to give 10.7 g of the title compound as anorange powder.

Physical characteristics are as follows:

MP 196-198° C.;

¹H NMR (400 MHz, DMSO) δ8.55, 7.89, 7.83, 2.82;

MS (ESI+)m/e 276 (M+H), 278.

EXAMPLE 595-Chloro-8-hydroxy-2-methyl-N-(2-pyridinylmethyl)-7-quinolinesulfonamide(Formula P-3 where R=CH₂2-pyridyl) Refer to Chart P

The title compound of Preparation 23 (0.300 g) is added to a solution of2-(aminomethyl)pyridine (0.23 mL) and N,N-diisopropylethylamine (0.58mL) in 4 mL of chlorobenzene and warmed to 140° C. for 2 h. The reactionmixture is then allowed to cool to room temperature and diluted with 75mL of EtOAc. The organic layer is washed with three 25-mL portions ofhalf-sat'd NaH₂PO₄ (aq), washed with brine, dried over MgSO₄, filteredand concentrated to give a white solid. Crystallization fromCH₂Cl₂/hexanes yields 0.205 g of the title compound as white crystals.

Physical characteristics are as follows:

MP 185-186° C.;

¹H NMR (300 MHz, DMSO) δ8.39, 8.30, 8.08, 7.72, 7.70, 7.60, 7.37,7.11-7.07, 4.22, 2.76 ppm;

¹³C NMR (75 MHz, DMSO) δ159.1, 157.0, 150.9, 148.4, 138.4, 136.4, 132.7,126.0, 125.9, 123.9, 122.3, 122.1, 121.4, 118.1, 47.8, 24.4 ppm;

IR (mull) 3331, 1445, 1395, 1327, 1305, 1157, 1143, 1062, 1015, 838,833, 825, 643, 632, 610 cm⁻¹;

MS (EI ) m/z 363 (M+), 195, 194, 193, 165, 164, 129, 128, 108, 107, 79;

HRMS (FAB) found 364.0523;

Anal. Found: C, 52.54; H, 4.00; N, 11.41; Cl, 9.59; S, 8.63.

EXAMPLE 605-Chloro-N-[2-(4-chlorophenyl)ethyl]-8-hydroxy-2-methyl-7-quinolinesulfonamide(Formula P-3 where R=CH₂CH₂4-ClC₆H₄) Refer to Chart P

The title compound is prepared according to the procedure described inExample 59, substituting 2-(4-chlorophenyl)ethylamine for2-(aminomethyl)pyridine. Crystallization from HOAc/H₂O/EtOH gives 0.409g of the title compound as light orange crystals.

Physical characteristics are as follows:

MP 131-133° C.;

¹H NMR (300 MHz, CDCl₃) δ8.45, 7.91, 7.57, 7.12, 6.99, 5.08, 3.27-3.21,2.82, 2.78 ppm;

¹³C NMR (75 MHz, DMSO) δ159.1, 150.8, 130.5, 137.7, 132.8, 130.6, 130.4,127.8, 125.8, 125.9, 123.8, 122.2, 118.1, 43.8, 34.4, 24.4 ppm;

IR (mull) 3366, 3346, 1492, 1428, 1346, 1328, 1317, 1246, 1162, 1143,1083, 1020, 830, 726, 643 cm⁻¹;

MS (El) m/z 410 (M+), 287, 285, 258, 256, 208, 195, 194, 193, 192, 164;

Anal. Found: C, 52.40; H, 4.07; N, 6.72; Cl, 17.00.

EXAMPLE 615-Chloro-8-hydroxy-2-methyl-N-(4-phenylbutyl)-7-quinolinesulfonamide(Formula P-3 where R=(CH₂)₄Ph) Refer to Chart P

The title compound is prepared according to the procedure described inExample 59, substituting 4-phenylbutylamine for 2-(aminomethyl)pyridine.Column chromatography on silica gel (elution with 25% EtOAc/hexanes and0-0.5% MeOH/CH₂Cl₂) gives 0.422 g of the title compound as an orangesolid.

Physical characteristics are as follows:

MP 84-86° C.;

¹H NMR (300 MHz, CDCl₃) δ8.45, 7.94, 7.57, 7.25-7.12, 7.07, 5.06-5.04,2.96, 2.80, 2.54, 1.65-1.48 ppm;

¹³C NMR (75 MHz, DMSO) δ223.3, 159.15, 150.81, 141.8, 138.5, 132.8,128.1, 128.0, 126.0, 125.9, 125.4, 123.9, 122.5, 118.1, 42.2, 34.5,28.7, 27.8, 24.0 ppm;

IR (mull) 3368, 3296, 1504, 1418, 1342, 1327, 1251, 1149, 1143, 1087,952, 771, 701, 669, 612 cm⁻¹;

MS (EI ) m/z 404 (M+), 219, 208, 195, 194, 193, 192, 164, 148, 131, 91;

HRMS (EI) found 404.0965;

Anal. Found: C, 59.63; H, 5.39; N, 6.79.

EXAMPLE 625-Chloro-8-hydroxy-2-methyl-N-[2-(2-pyridinyl)ethyl]-7-quinolinesulfonamide(Formula P-3 where R=CH₂CH₂2-pyridyl) Refer to Chart P

The title compound is prepared according to the procedure described inExample 59, substituting 2-(2-aminoethyl)pyridine for2-(aminomethyl)pyridine. Crystallization from EtOAc/hexanes gives 0.374g of the title compound as a light yellow solid.

Physical characteristics are as follows:

MP 153-155° C.;

¹H NMR (300 MHz, DMSO) δ8.41, 8.35, 7.73, 7.57, 7.17, 7.08, 3.23, 2.84,2.76 ppm;

¹³C NMR (75 MHz, DMSO) δ159.2, 158.3, 150.8, 148.7, 138.5, 136.3, 132.8,126.0, 125.9, 123.9, 123.2, 122.0, 121.4, 118.2, 42.2, 37.1, 24.4 ppm;

IR (mull) 1422, 1335, 1314, 1161, 1152, 1138, 1086, 1058, 948, 884, 824,819, 781, 771, 611 cm⁻¹;

MS (EI) m/z 377 (M+), 377, 256, 208, 195, 193, 192, 164, 121, 94, 93;

Anal. Found: C, 53.94; H, 4.33; N, 10.93.

Preparation 24 5,7-Dibromo-8-methoxy-2-(2-phenylethenyl)quinoline(Formula Q-2) Refer to Chart Q

A mixture of 5,7-dibromo-2-methyl-8-methoxyquinoline (10.29 g) andbenzaldehyde (15.84 g) is heated at reflux for 18 hrs. Upon cooling toroom temperature, a precipitate forms. Methanol is added, and thereaction mixture is sonicated. The solid material is then collected byfiltration. Crystallization from hot absolute ethanol yields 10.872 g ofthe title compound as a yellow solid.

Physical characteristics are as follows:

MP 150-152° C.;

¹H NMR (300 MHz, CDCl₃) δ8.42, 7.91, 7.81-7.73, 7.66, 7.47-7.35, 4.25ppm;

¹³C NMR (75 MHz, CDCl) δ156.3, 153.3, 143.6, 136.3, 136.2, 135.8, 132.8,129.0, 128.9, 128.2, 127.4, 127.0, 120.8, 116.5, 116.1, 62.5 ppm;

IR (mull) 3061, 3023, 1589, 1495, 1487, 1311, 1143, 993, 971, 966, 913,865, 819, 745, 685 cm⁻¹;

MS (EI) m/z 417 (M+), 421, 420, 419, 418, 417, 416, 390, 308, 228, 107;

Anal. Found: C, 51.22; H, 3.27; N, 3.32.

EXAMPLE 63(E)-5-Chloro-8-hydroxy-2-(2-phenylethenyl)-N-[2-(phenylthio)-ethyl]-7-quinolinesulfonamide(Formula Q-3, R=CH₂CH₂SPh) Refer to Chart Q

The title compound is prepared according to the procedures described inPreparations 6-8 and Example 17, substituting the title compound ofPreparation 24 for 5,7-dibromo-8-methoxy-2-methylquinoline inPreparation 6 and 2-aminoethyl phenyl sulfide for 4-chlorobenzylamine inPreparation 8. Triteration with hot EtOH gives 0.282 g of the titlecompound as a tan solid.

Physical characteristics are as follows:

MP 187-193° C.;

¹H NMR (300 MHz, CDCl₃) δ8.51, 7.90-7.88, 7.79, 7.67, 7.50-7.38,7.26-7.08, 5.61, 3.19-3.15, 3.07-3.04 ppm;

¹³ C NMR (75 MHz, CDCl₃) δ155.9, 151.7, 139.5, 137.3, 136.6, 135.5,133.9, 129.6, 129.5, 128.5, 127.9, 127.1, 127.0, 126.3, 125.0, 124.6,122.9, 118.9, 42.5, 32.3 ppm;

IR (mull) 3275, 3246, 1597, 1440, 1420, 1342, 1326, 1162, 1149, 1145,749, 693, 668, 633, 607 cm⁻¹;

MS (EI) m/z 496 (M+), 373, 344, 325, 323, 296, 282, 281, 280, 217, 216;

HRMS (EI) found 496.0670;

Anal. Found: C, 60.08; H, 4.37; N, 5.50.

EXAMPLE 645-Chloro-8-hydroxy-N-[2-l1H-indol-3-yl)ethyl]-2-methyl-7-quinolinesulfonamide(Formula J-5 where X¹=Cl, R¹=Me and R²=CH₂CH₂3-indolyl) Refer to Chart J

The title compound is prepared in two steps from5-bromo-8-methoxy-2-methyl-7-quinoline sulfonyl chloride according tothe procedures described in Preparation 8 and Example 17, substituting3-(2-aminoethyl)indole for 4-chlorobenzylamine in the former procedure.Preparative HPLC gives 0.082 g of the title compound as a tan solid.

Physical characteristics are as follows:

MP 163-165° C.;

¹H NMR (300 MHz, CDCl₃) δ8.44, 8.07, 7.90, 7.53, 7.26-7.20, 7.05,7.01-6.90, 6.77-6.72, 3.35-3.31, 2.99-2.94, 3.81 ppm;

¹³C NMR (75 MHz, CDCl₃) δ159.7, 151.4, 139.1, 136.6, 133.3, 127.3,126.6, 126.4, 124.5, 123.4, 122.8, 121.3, 118.8, 118.6, 118.3, 111.8,111.3, 44.0, 26.0, 24.9 ppm;

IR (mull) 3397, 3302, 1666 , 1552, 1488, 1425, 1331, 1306 , 1302 , 1200,1175, 1143, 745, 638, 601 cm⁻¹;

MS (EI) m/z 415 (M+), 322, 285, 256, 208, 193, 143, 131, 130, 103, 77;

HRMS (EI) found 415.0750.

Preparation 25 5-Chloro-8-hydroxy-7-iodo-2-methylquinoline (Formula R-2)Refer to Chart R

Iodine monochloride (19.0 g) is added to a solution of5-chloro-8-hydroxy-2-methylquinoline (21.5 g) in 250 mL of MeOH, and theresulting mixture is stirred for 3 h. Additional iodine monochloride(4.5 g) is then added, and the mixture is stirred for another 18 h. Thereaction mixture is quenched with sat'd Na₂SO₃ (aq), then neutralizedwith sat'd NaHCO₃ (aq). The solid precipitate is collected by filtrationand dried under vacuum to give 31.22 g of the title compound as a palegreen solid.

Physical characteristics are as follows:

MP 85-93° C.;

¹H NMR (300 MHz, DMSO) δ8.33, 7.88, 7.61, 2.72 ppm;

IR (mull) 3383, 1589, 1434, 1403, 1344, 1322, 1315, 1255, 1249, 1190,1137, 947, 719, 617, 607 cm⁻¹;

MS (ESI+) m/z 320 (M+H)⁺;

MS (ESI−) m/z 318 (M−H)⁻.

Preparation 26 5-Chloro-8-hydroxy-2-methyl-7-quinolinesulfinic acid(Formula R-3) Refer to Chart R

A solution of 5-chloro-8-hydroxy-7-iodo-2-methylquinoline (30.8 g) in500 mL of THF is cooled to −78° C., and methyl magnesium bromide (34.4mL of 3.0 M solution in ether) is added over 12 min. The resultingmixture is stirred for 20 min, then n-butyllithium (65 mL of 1.6 Msolution in pentane) is added over 25 min. The reaction mixture isallowed to stir at −78° C. for 2 h, then SO₂ (g) is introduced via aneedle positioned above the reaction surface. After 42 min, the reactionmixture turns a yellow opaque color and gas introduction is terminated(pH =5-6). Sat'd NaHCO₃ (aq) is added until the pH=8, and theprecipitate is collected by filtration. The aqueous layer of thefiltrate is separated, and the pH is adjusted to 4 with 10% HCl (aq).Gradually, a precipitate forms. This is collected by filtration toafford 8.73 g of the title compound as an orange solid.

Physical characteristics are as follows:

¹H NMR (300 MHz, DMSO) δ8.43, 7.73, 7.70, 2.76 ppm;

MS (ESI−) m/z 256 (M−H)⁻.

Preparation 27 5-Chloro-8-hydroxy-2-methyl-7-quinolinesulfonyl chloride(Formula R-4) Refer to Chart R

N-Chlorosuccinimide (2.07 g) is added to a solution of the titlecompound of Preparation 26 (4.0 g) in 70 mL of CH₂Cl₂, and the resultingmixture is stirred at room temperature for 2 h. The yellow-orange solidprecipitate is collected by filtration and dried under vacuum at 56° C.for 1.5 h to afford 2.75 g of the title compound, which is usedimmediately without further purification.

Preparation 285-Chloro-8-hydroxy-2-methyl-N-[2-(4-aminophenyl)ethyl]-7-quinolinesulfonamide(Formula R-5) Refer to Chart R

A solution of the title compound of Preparation 27 (1.51 g),2-(4-aminophenyl)ethylamine (0.68 mL), and pyridine (0.83 mL) in 30 mLof CH₂Cl₂ is stirred at room temperature for 18 h. The resultingprecipitate is isolated by filtration and rinsed with CH₂Cl₂ to give1.82 g of the title compound as an orange solid which is used withoutfurther purification.

Physical characteristics are as follows:

MP 249-253° C.;

¹H NMR (300 MHz, CDCl₃) δ8.31, 7.70, 7.65, 7.07-6.98, 2.94-2.84, 2.70,2.69-2.63 ppm.

EXAMPLE 655-Chloro-8-hydroxy-2-methyl-N-[2-[4-[[(3,5-dimethyl-4-isoxazolyl)sulfonyl]amino]phenyl]ethyl]-7-quinolinesulfonamide(Formula R-6, R=3,5-dimethyl-4-isoxazolyl) Refer to Chart R

A solution of the title compound of Preparation 28 (0.62 g) and3,5-dimethyl-isoxazole-4-sulfonyl chloride (0.31 mL) in 5 mL of pyridineis stirred at room temperature for 54 h. Additional sulfonyl chloride(0.31 mL) is added at 18 h and 36 h. The reaction mixture is thenconcentrated in vacuo, and the residue is partitioned between EtOAc, pH4 phosphate buffer and water. The organic layer is separated andconcentrated in vacuo to give 1.22 g of an orange solid. Columnchromatography on 75 g of silica gel (elution with 0-20% MeOH/CHCl)followed by crystallization from CH₂Cl₂/hexanes provides 0.041 g of thetitle compound as a yellow solid.

Physical characteristics are as follows:

MP 147-152° C. (decomposition);

¹H NMR (300 MHz, CDCl₃) δ8.39, 7.89, 7.47, 7.15, 7.08, 2.95, 2.73, 2.57,2.50, 2.48 ppm;

IR (mull) 1608, 1594, 1506, 1413, 1269, 1234, 1202, 1169, 1147, 1129,1071, 807, 796, 637, 611 cm⁻¹;

MS (EI) m/z 551 (MH+), 553, 552, 551, 153, 139, 123, 106, 105, 103, 91;

HRMS (EI) found 551.0850.

EXAMPLE 665-Chloro-8-hydroxy-2-methyl-N-[2-[4-[(phenylsulfonyl)amino]-phenyl]ethyl]-7-quinolinesulfonamide(Formula R-6, R=Ph) Refer to Chart R

The title compound is prepared according to the procedure described inExample 65, substituting benzenesulfonyl chloride for3,5-dimethylisoxazole-4-sulfonyl chloride. Column chromatography(elution with 0-10% MeOH/CHCl₃) followed by trituration with CHCl₃ gives0.247 g of the title compound as an off-white solid.

Physical characteristics are as follows:

MP 269-272° C.;

¹H NMR (300 MHz, CDCl₃) δ8.08, 7.32, 7.68-7.53, 6.92, 6.86, 2.90, 2.78,2.64 ppm;

¹³C NMR (75 MHz, DMDO) δ223.2, 184.1, 165.3, 154.8, 145.3, 140.2, 137.4,133.7, 132.3, 132.2, 129.0, 128.7, 127.5, 126.3, 124.4, 123.9, 121.3,116.8, 104.9, 43.7, 34.3, 24.2 ppm;

IR (mull) 3231, 1532, 1510, 1394, 1329, 1309, 1296, 1266, 1159, 1147,1126, 1108, 1094, 708, 691 cm⁻¹;

MS (EI) m/z 531 (M+), 195, 193, 167, 165, 164, 130, 107, 106, 77, 64.

Preparation 29 5-fluoro-8-hydroxy-7-quinolinesulfonyl chloride (FormulaS-2) Refer to Chart S

A solution of 5-fluoro-8-hydroxyquinoline (0.50 g) in 4.0 mL ofchlorosulfonic acid is stirred for 3 h at 90° C. and then 13 h at 105°C. The mixture is then cooled to 0° C. and poured onto 50 mL of finelydivided −15° C. ice. The bright orange-red precipitate is collected byfiltration, washed with four 10-mL portions of 0° C. distilled water andthree 2 mL portions of diethyl ether, and dried in a stream of air togive 0.208 g of the title compound as a red-orange powder.

Physical characteristics are as follows:

MP 248-250° C. (decomposition);

Anal. found: C, 41.01; H, 2.05; N, 5.32; S, 12.25.

EXAMPLE 67 5-Flouro-8-hydroxy-N-(phenylmethyl)7-quinoline sulfonamide(Formula 8-3) Refer to Chart S

A suspension of 5-fluoro-8-hydroxy-7-quinolinesulfonyl chloride (0.150g) in 2 mL of THF is cooled to −78° C. and treated with benzylamine(0.186 mL). The mixture is allowed to warm to 25° C. over several hours,then diluted with 50 μL of glacial acetic acid and 2 mL of distilledwater. The oil which forms is crystallized by scratching, and theresulting suspension is stirred for one hour. The solid is filtered,washed with two 2 mL portions of distilled water and dried in a streamof air to give 0.121 g of the title compound as a solid.

Physical characteristics are as follows:

MP 185.5-186° C.;

¹H NMR (400 MHz, DMSO) δ9.04, 8.48, 8.03, 7.81, 7.47, 7.22, 7.11, 7.03,4.12;

MS (ESI, positive ion mode) m/e 333 (M+H).

EXAMPLE 685-Chloro-N-[(4-chlorophenyl)methyl]-8-hydroxy-2-methyl-7-quinolinecarboxamide

To a solution of 5-chloro-8-hydroxy-2-methyl-7-quinolinecarboxylic acid(0.500 g) and 4-chlorobenzylamine (0.28 mL) in 20 ml, DMF is added EDChydrochloride (0.444 g) and hydroxybenzotriazole hydrate (0.312 g). Thereaction is stirred at room temperature for 48 h. The mixture is thenpartitioned between EtOAc and water. The aqueous layer is extracted withEtOAc (3×). The combined organic layers are washed with brine (1×),dried over sodium sulfate and condensed. The residue is stirred in 20 mL1:1 THF/1N HCl overnight. The solution is neutralized with saturatedaqueous NaHCO₃. The reaction is partitioned between EtOAc and water. Theaqueous layer is extracted with EtOAc (3×). The combined organic layersare washed with brine (1×), dried and condensed. The crude product ischromatographed on silica, eluting with 3% MeOH/CH₂Cl₂. Fractionshomogeneous by TLC are combined and condensed. The residue taken up in aminimal amount of CH₂Cl₂. Toluene is added to the solution and themixture is sonicated while adding hexanes until a white solid formed.The solid is collected and dried to yield 0.310 g of the title productas a white solid.

Physical characteristics are as follows:

MP 128-130° C.;

¹H NMR (300 MHz, DMSO-d₆) δ9.54, 8.35, 8.09, 7.66, 7.39, 4.54, 2.71;

IR (mull) 3399, 3299, 1660, 1603, 1565, 1531, 1500, 1492, 1428, 1350,1332, 1251, 1226, 798, 630 cm⁻¹.

MS (EI) m/z 360 (M+), 362, 360, 221, 220, 195, 194, 193, 164, 140, 125.

Anal. Found: C, 59.53; H, 4.11; N, 7.71; Cl, 19.38.

EXAMPLE 695-chloro-8-hydroxy-2-methyl-N-(3-phenylpropyl)-7-quinolinecarboxamide

To a solution of 5-chloro-8-hydroxy-2-methyl-7-quinolinecarboxylic acid(0.500 g) and 3-phenylpropylamine (0.33 mL) in 20 mL DMF is added EDChydrochloride (0.444 g) and hydroxybenzotriazole hydrate (0.312 g). Thereaction is stirred at room temperature for 48 h. The mixture is thenpartitioned between EtOAc and water. The aqueous layer is extracted withEtOAc (3×). The combined organic layers are washed with brine (1×),dried over sodium sulfate and condensed. The residue is stirred in 20 mL1:1 THF/1N HCl overnight. The solution is neutralized with saturatedaqueous NaHCO₃. The reaction is partitioned between EtOAc and water. Theaqueous layer is extracted with EtOAc (3×). The combined organic layersare washed with brine (1×), dried and condensed. The crude product ischromatographed on silica, eluting with 3% MeOH/CH₂Cl₂. Fractionshomogeneous by TLC are combined and condensed. The residue taken up in aminimal amount of CH₂Cl₂. Toluene is added to the solution and themixture is sonicated while adding hexanes until a white solid formed.The solid is collected and dried to yield 0.310 g of the title productas a white solid.

Physical characteristics are as follows:

MP 109-111° C.;

¹H NMR (300 MHz, DMSO-d₆) δ8.95, 8.36, 8.08, 7.66, 7.30-7.16, 3.35,2.71, 2.65, 1.87;

IR (mull) 3305, 1638, 1602, 1574, 1556, 1503, 1496, 1424, 1350, 1319,1302, 1265, 943, 745, 698 cm⁻¹.

MS (EI) m/z 354 (M⁺), 354, 250, 222, 221, 220, 195, 194, 193, 164, 91.

Anal. Found: C, 67.75; 11, 5.48; N, 7.81; Cl, 9.92.

EXAMPLE 705-chloro-8-hydroxy-2-methyl-N-[(2-phenylthio)ethyl]-7-quinolinecarboxamide

To a solution of 5-chloro-8-hydroxy-2-methyl-7-quinolinecarboxylic acid(0.500 g) and aminoethylphenyl sulfide (0.354 g) in 20 mL DMF is addedEDC hydrochloride (0.444 g) and hydroxybenzotriazole hydrate (0.312 g).The reaction is stirred at room temperature for 48 h. The mixture isthen partitioned between EtOAc and water. The aqueous layer is extractedwith EtOAc (3×). The combined organic layers are washed with brine (1×),dried over sodium sulfate and condensed. The residue is stirred in 20 mL1:1 THF/1 N HCl overnight. The solution is neutralized with saturatedaqueous NaHCO₃. The reaction is partitioned between EtOAc and water. Theaqueous layer is extracted with EtOAc (3×). The combined organic layersare washed with brine (1×), dried and condensed. The residue taken up ina minimal amount of CH₂Cl₂. Toluene is added to the solution and themixture is sonicated while adding hexanes until a solid formed. Thesolid is collected and dried to yield 0.499 g of the title product as anoff-white solid.

Physical characteristics are as follows:

MP 131-134° C.;

¹H NMR (300 MHz, DMSO-d₆) δ9.28, 8.35, 8.02, 7.66, 7.41, 7.30, 7.17,3.55, 3.19, 2.71;

IR (mull) 3322, 1631, 1612, 1602, 1567, 1553, 1501, 1483, 1439, 1423,1341, 1317, 1268, 1247, 744 cm⁻¹.

MS (EI) m/z 372 (M⁺), 372, 238, 236, 222, 221, 220, 219, 164, 136, 135.

HRMS (EI) found 372.0701.

EXAMPLE 718-hydroxy-N-[5-[[[4-(1-methylethyl)phenylsulfonyl]amino]-pentyl]-7-quinolinecarboxamide

To a solution of 8-hydroxyquinoline-7-carboxylic acid (0.147 g) andN-(5-aminopentyl)-4-(1-methylethyl)benzenesulfonamide monohydrochloride(0.250 g) in 5 mL DMF is added EDC hydrochloride (0.149 g) andhydroxybenzotriazole hydrate (0.105 g), followed bydiisopropylethylamine (0.271 mL). The reaction is stirred overnight atroom temperature, then poured into 50 mL water. The resulting solutionis partitioned between EtOAc and water. The aqueous layers are extractedwith EtOAc (3×). The combined organic layers are washed with brine (1×),dried over sodium sulfate and condensed. The crude product ischromatographed on silica, eluting with 3% MeOH/CH₂Cl₂. Fractionshomogeneous by TLC are combined, concentrated and recrystallized fromacetone/hexanes to yield 0.060 g of the title product as a gold solid.

Physical characteristics are as follows:

MP 106-108° C.;

¹H NMR (300 MHz, DMSO-d₆) δ8.89, 8.79, 8.31, 7.94, 7.68, 7.62,7.49-7.38, 3.27, 2.93, 2.71, 1.49, 1.38, 1.27, 1.18;

MS (EI) m/z 455 (M⁺), 283, 266, 255, 189, 173, 172, 171, 145, 116, 84.

HRMS (EI) found 455.1875.

Anal. Found: C, 62.61; 1, 6.39; N, 9.00.

EXAMPLE 72 N-(cyanomethyl)-8-hydroxy-7-quinolinecarboxamide

8-hydroxyquinoline-7-carboxylic acid (0.51 g), aminoacetonitrile HCl(0.27 g), and triethylamine (0.38 ml) are dissolved in 10 mLdimethylformamide. EDC.HCl (0.54 g) and HOBt.H₂O (0.38 g) are added andthe reaction is stirred at room temperature for 2 days. The reaction ispoured into 50 mL ice/H₂O and stirred. After approximately 30 minutes, asolid is collected and dried. The desired product is recrystallized fromethyl acetate (0.12 g).

Physical characteristics are as follows:

MP 206-208° C. (dec);

¹H NMR (300 MHz, DMSO-d₆) δ9.26, 8.93, 8.39, 7.96, 7.68, 7.44, 4.40.

IR (mull) 3309, 3284, 1645, 1625, 1536, 1405, 1397, 1345, 1301, 1279,1264, 1205, 846, 785, 723 cm⁻¹.

MS (electrospray) 228.2 (M+H₁), 250.1 (M+Na), 226.1 (M−H₁).

Anal. Found: C, 63.43; H, 4.14; N, 18.40.

EXAMPLE 738-hydroxy-N-(2-hydroxy-2-phenylethyl)-2-[2-(4-methoxyphenyl)-ethyl]-7-quinolinecarboxamide

The title compound of Example 53 (0.090 g) is dissolved in 6 mL 1:1THF:MeOH. Triethylamine (0.04 ml) followed by 20 mg 10% Pd/C is added tothe reaction mixture. The reaction is placed under a hydrogen balloonand stirred at room temperature for 2 hours. The reaction is filteredover Celite and the filter cake rinsed thoroughly with ethyl acetate.The filtrate is evaporated under reduced pressure to give a solid whichis then recrystallized from EtOAc/hexanes very slowly. The resultingsolid is filtered and dried to give the desired product (0.048 g).

Physical characteristics are as follows:

MP 69-72° C.;

¹H NMR (300 MHz, DMSO-d₆) δ8.95, 8.20, 7.94, 7.51, 7.41, 7.33, 7.25,7.17, 6.81, 4.82, 3.68, 3.62, 3.39, 3.21, 3.06.

IR (mull) 3398, 1636, 1603, 1549, 1512, 1425, 1344, 1241, 1179, 1064,1032, 839, 744, 729, 698 cm⁻¹.

MS (electrospray) 443.1 (M+H₁), 465.0 (M+Na), 441.0 (M−H₁).

HRMS (FAB) found 443.1985.

Anal. Found: C, 70.43; H, 5.96; N, 6.03.

Preparation 30 8-Hydroxyquinoline, 7-carboxylic acid (formula T-2) Referto Chart T

A finely ground mixture of 27.8 g of 8-hydroxyquinoline (T-1) and 79.2 gof potassium carbonate is placed in a bomb and heated to 175° C. under800 psi carbon dioxide gas. After seven days, the reaction is cooled toroom temperature. The resulting mixture is treated with 1.2 L of hotwater to dissolve most of the material. The suspension is filtered,cooled to room temperature and acidified to pH=7 with concentratedhydrochloric acid. The precipitate is removed by filtration. Thefiltrate is acidified to pH=3.5 with concentrated hydrochloric acid. Thenew precipitate is collected by suction filtration, washed withrepeatedly isopropanol followed by hexanes. The yellow solid is dried invacuo to afford 26 g of the title acid.

Physical characteristics are as follows:

1H-NMR (DMSO): 8.9, 8.6, 7.9, 7.8, 7.3.

EXAMPLE 74 N-[2-(3-Chlorophenyl)ethyl]-8-hydroxy-7-quinolinecarboxamide(uninverted CAS name) (formula T-3 wherein R⁰ is2-(3-chlorophenyl)ethyl) Refer to Chart T

To a suspension of 1.89 g of T-2 of Preparation 30, 1.50 g of1-hydroxbenzotriazole and 2.30 g of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 50 mL ofdichloromethane is added 1.55 mL of 2-(3-chlorophenyl)ethylamine. Thereaction is stirred overnight at room temperature. The resulting orangesolution is diluted with dichloromethane and partioned against saturatedaqueous sodium bicarbonate. The aqueous phase is extracted withadditional portions of dichloromethane. The organic layers are combinedand washed with pH=4 aqueous phosphate buffer followed by brine. Theorganic phase is dried over anhydrous magnesium sulfate, filtered andconcentrated under reduced pressure. The residue is crystallized fromethyl acetate to afford 2.55 g of the title compound.

Physical characteristics are as follows:

1H-NMR (CDCl₃): 10.0, 8.8, 8.2, 8.0, 7.5, 7.3, 7.2, 7.1, 3.8, 3.0;

Elem. Anal.: C 65.82, H 4.63, N 8.56;

MS-ESI: 327 (+mode), 325 (−mode).

EXAMPLES 75-151

Following similar procedures to those described above, these additionalanalogues are prepared:

8-Hydroxy-N-[2-(3-indolyl)ethyl)-7-quinolinecarboxamide;

8-Hydroxy-N-[2-(4-hydroxyphenyl)ethyl]-7-quinolinecarboxamide;

8-Hydroxy-N-[2-(2-[4-phenoxy]phenyl)ethyl]-7-quinolinecarboxamide;

N-[(2,4-Dichlorophenyl)methyl]-8-hydroxy-7-quinolinecarboxamide;

N-[(3,4-Dichlorophenyl)methyl]-8-hydroxy-7-quinolinecarboxamide;

N-Decyl-8-hydroxy-7-quinolinecarboxamide;

8-Hydroxy-N-(4-phenylbutyl)-7-quinolinecarboxamide;

8-Hydroxy-N-octyl-7-quinolinecarboxamide;

8-Hydroxy-N-[[4-(trifluoromethyl)phenyl]methyl]-7-quinolinecarboxamide;

8-Hydroxy-N-[[2-(trifluoromethyl)phenyl]methyl]-7-quinolinecarboxamide;

N-[2-(1-Cyclohexenyl)ethyl]-8-hydroxy-7-quinolinecarboxamide;

N-[2-(2,4-Dichlorophenyl)ethyl]-8-hydroxy-7-quinolinecarboxamide;

8-Hydroxy-N-(cis-myrtanyl)-7-quinolinecarboxamide;

N-[(2-Chlorophenyl)methyl]-8-hydroxy-7-quinolinecarboxamide;

8-Hydroxy-N-[(2-methylphenyl)methyl]-7-quinolinecarboxamide;

8-Hydroxy-N-[(3-methylphenyl)methyl]-7-quinolinecarboxamide;

N-[(4-Chlorophenyl)methyl]-8-hydroxy-7-quinolinecarboxamide;

8-Hydroxy-N-(2-hydroxy-2-phenylethyl)-7-quinolinecarboxamide;

N-(2,2-Diphenylethyl)-8-hydroxy-7-quinolinecarboxamide;

8-Hydroxy-N-(2-phenylpropyl)-7-quinolinecarboxamide;

N-[1-(2-Ethyl)hexyl]-8-hydroxy-7-quinolinecarboxamide;

8-Hydroxy-N-undecyl-7-quinolinecarboxamide;

8-Hydroxy-N-octadecyl-7-quinolinecarboxamide;

N-[2-(4-Bromophenyl)ethyl]-8-hydroxy-7-quinolinecarboxamide;

N-[2-(4-Chlorophenyl)ethyl]-8-hydroxy-7-quinolinecarboxamide;

8-Hydroxy-N-[2-(4-methylphenyl)ethyl]-7-quinolinecarboxamide;

N-(3,3-Diphenylpropyl)-8-hydroxy-7-quinolinecarboxamide;

8-Hydroxy-N-(3-phenylpropyl)-7-quinolinecarboxamide;

8-Hydroxy-N-nonyl-7-quinolinecarboxamide;

N-[(2,6-Difluorophenyl)methyl]-8-hydroxy-7-quinolinecarboxamide;

N-[(3-Chlorophenyl)methyl]-8-hydroxy-7-quinolinecarboxamide;

8-Hydroxy-N-(2-methylcyclohexyl)-7-quinolinecarboxamide;

N-(2,3-Dimethylcyclohexyl)-8-hydroxy-7-quinolinecarboxamide;

8-Hydroxy-N-(3-methylcyclohexyl)-7-quinolinecarboxamide;

8-Hydroxy-N-(4-methylcyclohexyl)-7-quinolinecarboxamide;

8-Hydroxy-N-[(1,2,3,4-tetrahydro-1-naphthalenyl)methyl]-7-quinolinecarboxamide;

N-Cyclooctyl-8-hydroxy-7-quinolinecarboxamide;

8-Hydroxy-N-(1-indanyl)-7-quinolinecarboxamide;

N-Cycloheptyl-8-hydroxy-7-quinolinecarboxamide;

8-Hydroxy-N-(diphenylmethyl)-7-quinolinecarboxamide;

8-Hydroxy-N-(1-phenylethyl)-7-quinolinecarboxamide;

N-(2-Heptyl)-8-hydroxy-7-quinolinecarboxamide;

8-Hydroxy-N-(2-octyl)-7-quinolinecarboxamide;

N-(4-tert-Butylcyclohexyl)-8-hydroxy-7-quinolinecarboxamide;

S—N-[7-(7-Carboxy-8-hydroxy)quinolyl]-tyrosine, tert-butyl ester;

R-8-Hydroxy-N-[1-(1-naphthyl)ethyl]-7-quinolinecarboxamide;

S-8-Hydroxy-N-[1-(1-naphthyl)ethyl]-7-quinolinecarboxamide;

R-8-Hydroxy-N-(1-phenylethyl)-7-quinolinecarboxamide;

R—N-[1-(4-Bromophenyl)ethyl]-8-hydroxy-7-quinolinecarboxamide;

S—N-[1-(4-Bromophenyl)ethyl]-8-hydroxy-7-quinolinecarboxamide;

N-[2-((1S,2R)-1,2-Diphenyl-1-hydroxy)ethyl]-8-hydroxy-7-quinolinecarboxamide;

N-[2-((1R,2S)-1,2-Diphenyl-1-hydroxy)ethyl]-8-hydroxy-7-quinolinecarboxamide;

8-Hydroxy-N-(2-exo-norbornyl)-7-quinolinecarboxamide;

8-Hydroxy-N-[(4-hydroxy-3-methoxyphenyl)methyl]-7-quinolinecarboxamide;

S-8-Hydroxy-N-[2-(1-hydroxy-3-[4-hydroxyphenyl])propyl]-7-quinolinecarboxamide;

S—N-[7-(7-Carboxy-8-hydroxy)quinolyl]-serine, benzyl ester;

N-[7-(7-Carboxy-8-hydroxy)quinolyl]-tyrosine, methyl ester;

N-[7-(7-Carboxy-8-hydroxy)quinolyl]-tryptophan, ethyl ester;

N-(2-Adamantyl)-8-hydroxy-7-quinolinecarboxamide;

S—O-Benzyl-N-[7-(7-Carboxy-8-hydroxy)quinolyl]-tyrosine, methyl ester;

S—N-[7-(7-Carboxy-8-hydroxy)quinolyl]-4-nitrophenylalanine, methylester;

N-[(2,5-Difluorophenyl)methyl]-8-hydroxy-7-quinolinecarboxamide;

8-Hydroxy-N-[1-(1-hydroxymethyl)cyclopentyl]-7-quinolinecarboxamide;

N-[(3-Chloro-4-fluorophenyl)methyl]-8-hydroxy-7-quinolinecarboxamide;

N-[(2,3-Dichlorophenyl)methyl]-8-hydroxy-7-quinolinecarboxamide;

N-[(2,5-Dichlorophenyl)methyl]-8-hydroxy-7-quinolinecarboxamide;

N-(2-[([2-chloro-6-fluorophenyl]methyl)thio]ethyl)-8-hydroxy-7-quinolinecarboxamide;

N-[2-([(2,6-Dichlorophenyl)methyl])thio)ethyl]-8-hydroxy-7-quinolinecarboxamide;

N-[(2-Chloro-6-phenoxy-phenyl)methyl]-8-hydroxy-7-quinolinecarboxamide;

8-Hydroxy-N-[(2-[(2-[hydroxymethyl]phenyl)thio]phenyl)methyl]-7-quinolinecarboxamide;

8-Hydroxy-N-(2-[(4-[2-trifluoromethyl]quinolyl)thio]ethyl)-7-quinolinecarboxamide;

N-(Cyclohexylmethyl)-8-hydroxy-7-quinolinecarboxamide;

8-Hydroxy-N-(1-naphthalenylmethyl)-7-quinolinecarboxamide;

N-[2-(3-Chlorophenyl)ethyl]-8-hydroxy-7-quinolinecarboxamide;

8-Hydroxy-N-[[3-(trifluoromethyl)phenyl]methyl]-7-quinolinecarboxamide;

8-Hydroxy-N-[2-(phenylthio)ethyl]-7-quinolinecarboxamide; and

N-Heptyl-8-hydroxy-7-quinolinecarboxamide.

Preparation 31 N-Aryl-8-hydroxy-7-quinolinecarboxamides from anhydrideU-1, procedure for single compounds (GP II) (Refer to Chart U)

Anhydride U-1 (1 eq.) is dissolved in CHCl₃ (n mL) at r.t. Pyridiniumchloride (1 eq) and then the arylamine (about 1 eq.) are added. Thesolution is stirred for 6 h at r.t. 1M HCl/H₂O (n mL) is added and thebiphasic mixture is stirred efficiently overnight. The precipitate isfiltered, washed with a little water and CH₂Cl₂ and dried under highvacuum.

Preparation 32 N-Aryl-8-hydroxy-7-quinolinecarboxamides from anhydrideU-1, procedure for parallel synthesis (GP III) (Refer to Chart U)

The aryl amines (0.20 mmol) are laid into syringes corked at theiroutput and set with a frit at the bottom of their large section. A sol.of anhydride U-1 (0.1M) and pyridinium chloride (0.1M) in CHCl₃ isprepared. This solution (2 mL/syringe) is added into the syringes; ifthe arylamine is a liquid, it is added at this stage only; if thearylamine is a hydrochloride salt, DIPEA (33 μL, 1 eq) is added. Thesyringes are tightly closed at their bottoms and shaken for 6 h at r.t.1M HCl/H₂O (2 mL) is added and the biphasic mixture is shakenefficiently overnight. The precipitate is isolated by sucking thesolvent from the bottom of the syringes, washed with a little water andCH₂Cl₂ and dried under high vacuum.

Preparation 33 N-Aryl-8-hydroxy-7-quinolinecarboxamides from the esterU-3, procedure for single compounds (GP IV) (Refer to Chart U)

Ester U-3 is dissolved in CH₂Cl₂ and the arylamine (about 1 eq) andDIPEA (about 1 eq.) are added. The reaction mixture is stirred between 6h and 6 days. MeOH (same amount as CH₂C₂) is added and the mixture isstirred between 6 h and 18 h. For the work-up procedures, see specificexamples below.

Preparation 34 N-Aryl-8-hydroxy-7-quinolinecarboxamides from ester U-3,procedure for parallel synthesis (GP V) (Refer to Chart U)

The aryl amines (0.2 mmol) are put into syringes corked at their outputand set with a frit at the bottom of their large section. A sol. ofester 3 (0.05M) and DIPEA (0.05M) in CH₂Cl₂ is prepared and added to thearylamines (4 mL for each amine); if the arylamine is a liquid, it isadded at this stage only; if the arylamine is a salt, DIPEA (33 μL, 1eq) is added. The syringes are tightly closed and shaken for 5 days.MeOH (2-4 mL) is added and the mixture is shaken for 6 h. Theprecipitate, if any, is isolated by sucking the solvent from the bottomof the syringes, washed with AcOEt and dried under high vacuum(P-fraction). The filtrate is washed with sat. NaHCO₃/H₂O (1×) and anaq. buffer sol. at pH4 (1×); each time, the aq. phase is pipetted out ofthe seringe. If a precipitate appears during the work-up, it is filteredand dried (WU-fraction). The filtrate is blown down with a nitrogenstream; AcOEt (4 mL) is added and the mixture heated to 65° C. for 30min. and cooled to 0° C. The solvent is pipetted out and the residuedried under high vacuum (T-fraction). The org. phase is blown down andthe residue dried under high vacuum as well (S-fraction). The degree ofhydration of the obtained products was not determined.

Preparation 358-{[(2,2,2-Trichloroethoxy)carbonyl]oxy}-7-quinolinecarboxylic acidanhydride with 2,2,2-trichloroethyl hydrogen carbonate (U-1) (Refer toChart U)

In a flame-dried flask, 8-hydroxy-7-quinolinecarboxylic acid (2.00 g) issuspended into CH₂Cl₂ (100 mL) and DIPEA (3.70 mL) is added. The mixtureis stirred until homogeneity is reached and cooled to 0° C.Trichloroethyl chloroformate (3.00 mL) is added and the solution isstirred for 3 h at 0° C., then stirred for another hour while allowed towarm up slowly to r.t. The solution is washed with 1M HCl/H₂O (1×),dried over Na₂CO₃ and the solvent removed under reduced pressure.Crystallization of the residue from CHCl₃/hexanes yielded the desiredproduct (5.20 g).

Physical characteristics are as follows:

mp: 133-4° C.

¹H-NMR (CDCl₃, 300 MHz) δ9.05, 8.26, 8.11, 7.88, 7.61, 4.97, 4.95.

¹³C-NMR (CDCl₃, 75 MHz) δ: 157.56, 152.13, 151.59, 149.25, 147.71,141.09, 135.82, 132.64, 126.57, 126.45, 124.44, 119.67, 93.96, 93.42.

MS (FAB) m/z 538, 540 and 542 (MH⁺), 172.

HRMS (FAB): found: 537.8609.

Anal. Found: C, 35.12; H, 1.85; N, 2.65.

Preparation 36 8-Acetoxy-7-quinolinecarboxylic acid (U-2) (Refer toChart U)

This compound is prepared according to literature procedure (Germanpatent number 540842, Dec. 10, 1931).

Physical characteristics are as follows:

¹H-NMR (d₆-DMSO, 300 MHz) δ13.35, 8.99, 8.46, 8.00, 7.95, 7.67, 2.38.

¹³C-NMR (d₆-DMSO, 75 MHz) δ172.46, 169.22, 166.21, 152.08, 147.95,141.42, 136.61, 131.35, 127.08, 126.13, 124.07, 21.20.

Preparation 37 7-(Fluorocarbonyl)-quinolin-8-yl acetate (U-3) (Refer toChart U)

In a flame-dried flask under Ar, 8-acetoxy-7-quinolinecarboxylic acidU-2 (4.30 g) is suspended into CH₂Cl₂ (110 mL). Pyridine (1.50 mL) isadded and the suspension cooled to −40° C. Cyanuric fluoride (3.00 mL)is added and the mixture stirred for 3 h, while the temperature roseslowly to 0° C. Ice and water and CH₂Cl₂ (100 mL) are added. Phases areshaken, separated and the aq. phase extracted with CH₂Cl₂ (1×). Thecombined org. phases are dried over MgSO₄, filtered, and the solvent isremoved under reduced pressure. Crystallization of the residue fromhexanes yielded ester U-3 as white needles (4.10 g).

Physical characteristics are as follows:

mp: 130-132° C.

¹H-NMR (CDCl₃, 300 MHz) δ9.05, 8.22, 8.02, 7.80, 7.58, 2.58.

¹³C-NMR (CDCl₃, 75 MHz) δ169.06, 156.59, 151.89, 141.42, 136.07, 132.92,126.77, 126.03, 124.41, 118.10, 117.30, 20.88.

MS (FAB) m/z 234 (MH⁺), 192, 172.

HRMS (FAB): 234.0569.

Anal. C, 60.98; H, 3.55; N, 6.24.

EXAMPLE 152 8-Hydroxy-N-(4-methoxyphenyl)-7-quinolinecarboxamidemonohydrochloride (V-4) (Refer to Chart V)

According to GP II, starting from anhydride U-1 (50 mg), pyridiniumchloride (10.8 mg) and 4-methoxyaniline (11.4 μg) in CHCl₃ (2 mL), amideU-4 is obtained as a pale yellow precipitate (10 mg).

Physical characteristics are as follows:

¹H-NMR (CD₃OD, 300 MHz) δ9.15, 8.43, 8.18, 7.83, 7.63, 6.96, 3.82.

¹³C-NMR (CD₃OD, 75 MHz) δ167.37, 157.63, 153.46, 146.28, 144.61, 131.70,130.07, 129.69, 126.73, 123.92, 123.51, 117.56, 115.33, 113.67, 54.52.

MS (EI) m/z 294 (M⁺), 172, 123, 116, 108, 89.

HRMS (EI): 294.1003.

EXAMPLE 153 N-(4-Cyanophenyl)-8-hydroxy-7-quinolinecarboxamidemonohydrochloride (V-5) (Refer to Chart V)

According to GP II, starting with anhydride U-1 (200 mg), pyridiniumchloride (42 mg) and 4-aminobenzonitrile (44 mg) in CHCl₃ (8 mL), amideV-5 is obtained as a red powder (50 mg).

Physical characteristics are as follows:

¹H-NMR (d₆-DMSO, 300 MHz) δ11.8, 8.96, 8.68, 8.08, 7.94, 7.82, 7.45).

¹³C-NMR (d₆-DMSO, 75 MHz) δ166.42, 146.73, 143.49, 140.96, 133.77,131.59, 128.3, 124.18, 120.66, 119.51, 116.81, 115.57, 105.84.

MS (EI) m/z 289 (M⁺), 172, 116, 89.

HRMS (EI): 289.0848.

EXAMPLE 154 N-(3-Chlorophenyl)-8-hydroxy-7-quinolinecarboxamidemonohydrochloride (V-6) (Refer to Chart V)

According to GP II, starting from anhydride U-1 (200 mg), pyridiniumchloride (42 mg), 3-chloroaniline (39 μL) and CHCl3 (8 mL), amide V-6 isobtained as a yellow powder (50 mg).

Physical characteristics are as follows:

¹H-NMR (CD₃OD, 300 MHz) δ8.82, 8.28, 7.96, 7.90, 7.62, 7.36, 7.18.

¹³C-NMR (d₆-DMSO, 75 MHz) δ166.45, 155.03, 147.30, 140.94, 140.42,135.93, 133.56, 131.43, 130.95, 127.92, 124.23, 120.43, 119.35, 116.50.

MS (EI) m/z 298 and 300 (MH⁺), 172, 116.

Anal. Found: C, 57.09; H, 3.78; N, 8.28.

EXAMPLE 155N-[3,5-Bis(trifluoromethyl)phenyl]-8-hydroxy-7-quinolinecarboxamidemonohydrochloride (V-7) (Refer to Chart V)

According to GP II, starting from anhydride U-1 (200 mg), pyridiniumchloride (42 mg), 3,5-bis(trifluoromethyl)aniline (58 μL and CHCl₃ (8mL), amide V-7 is obtained as an orange powder (30 mg, 20%).

Physical characteristics are as follows:

¹H-NMR (d₆-DMSO, 300 MHz) δ11.90, 8.97, 8.64, 8.46, 8.05, 7.84, 7.81,7.47.

¹³C-NMR (d₆-DMSO, 75 MHz) δ166.77, 155.62, 147.30, 141.18, 140.21,131.55, 131.03, 127.94, 125.53, 124.23, 121.92, 120.37, 116.38.

MS (EI) m/z 400 (M⁺), 172, 116, 89.

HRMS (EI) 400.0653.

EXAMPLE 156 N-Fluoren-2-yl-8-hydroxy-7-quinolinecarboxamidemonohydrochloride (V-8) (Refer to Chart V)

According to GP II, starting from anhydride U-1 (200 mg), pyridiniumchloride (42 mg), 2-aminofluorene (67 mg) and CHCl₃ (8 mL), amide V-8 isobtained as a yellow powder (55 mg).

Physical characteristics are as follows:

¹H-NMR (CDCl₃, 300 MHz) δ11.10, 9.02, 8.69, 8.23, 8.07, 7.89, 7.84,7.72, 7.57, 7.36, 7.27.

¹³C-NMR (d₆-DMSO, 75 MHz) δ166.27, 154.91, 147.55, 144.24, 143.42,141.33, 140.72, 137.77, 137.67, 135.96, 131.34, 127.64, 127.25, 126.81,125.53, 124.25, 120.66, 120.12, 120.03, 118.04, 116.88, 116.31, 37.01.

MS (EI) m/z 352 (M⁺), 181, 172, 116, 89.

HRMS (EI) 352.1190.

EXAMPLE 157N-{[4-[(3,4-Dimethylisoxazol-5-ylamino)sulfonyl]phenyl}-8-hydroxy-7-quinolinecarboxamidemonohydrochloride (V-9) (Refer to Chart V)

According to GP II, starting from anhydride U-1 (200 mg), pyridiniumchloride (42 mg),4-amino-N-(3,4-dimethylisoxazol-5-yl)benzenesulfonamide (99 mg) andCHCl₃ (8 mL), amide V-9 is obtained as an orange powder (47 mg).

Physical characteristics are as follows:

¹H-NMR (d₆-DMSO, 300 MHz) δ11.85, 10.95, 8.94, 8.61, 8.04, 7.95, 7.81,7.75, 7.41, 2.08, 1.63.

¹³C-NMR (d₆-DMSO, 75 MHz) δ166.19, 161.90, 156.19, 155.99, 146.92,143.67, 140.05, 137.29, 134.44, 131.58, 128.47, 128.24, 124.08, 120.27,116.43, 115.20, 105.64, 10.80, 6.34.

MS (EI) m/z 438 (M⁺), 369, 343, 327, 263, 172, 156, 116.

HRMS (FAB) 439.1091.

EXAMPLE 158 N-1,3-Benzodioxol-5-yl-8-hydroxy-7-quinolinecarboxamidemonohydrochloride (V-10) (Refer to Chart V)

According to GP II, starting from anhydride U-1 (200 mg), pyridiniumchloride (42 mg), 5-amino-1,3-benzodioxol (51 mg) and CHCl₃ (8 mL),amide V-10 is obtained as a yellow powder (60 mg).

Physical characteristics are as follows:

¹H-NMR (d₆-DMSO, 300 MHz) δ10.95, 8.98, 8.64, 8.15, 7.82, 7.53, 7.44,7.11, 6.92, 6.02.

¹³C-NMR (d₆-DMSO, 75 MHz) δ166.21, 155.12, 147.72, 147.91, 144.02,140.15, 132.89, 131.28, 127.35, 124.19, 116.83, 115.92, 114.39, 108.55,103.40, 101.63, 61.06.

MS (EI) m/z 308 (M⁺), 172, 137, 116, 89.

HRMS (EI) 308.0797.

EXAMPLE 1598-Hydroxy-N-[4-(trifluoromethyl)coumarin-7-yl]-7-quinolinecarboxamidemonohydrochloride (V-11) (Refer to Chart V)

According to GP II, starting from anhydride U-1 (200 mg), pyridiniumchloride (42 mg), 7-amino-4-(trifluoromethyl)coumarin (85 mg) and CHCl₃(8 mL), amide V-11 is obtained as a yellow powder (25 mg).

Physical characteristics are as follows:

¹H-NMR (d₆-DMSO, 300 MHz) δ8.94, 8.65, 8.11, 8.05, 7.83, 7.71, 7.66,7.38, 6.91.

¹³C-NMR (d₆-DMSO, 75 MHz) δ166.40, 159.13, 155.28, 146.35, 143.73,140.72, 131.77, 128.52, 125.91, 124.11, 117.29, 116.40, 114.67, 114.57,108.91, 107.41.

MS (EI) m/z 400 (M⁺), 172, 116, 89.

HRMS (EI) 400.0664.

EXAMPLE 160 N-(3-Fluorophenyl)-8-hydroxy-7-quinolinecarboxamidemonohydrochloride (V-12) (Refer to Chart V)

According to GP II, starting from anhydride U-1 (200 mg), pyridiniumchloride (42 mg), 3-fluoroaniline (36 μL) and CHCl₃ (8 mL), amide V-12is obtained as a white powder (45 mg).

Physical characteristics are as follows:

¹H-NMR (d₆-DMSO, 300 MHz) δ11.35, 8.96, 8.62, 8.07, 7.83-7.76, 7.47,7.43, 7.39, 6.95.

¹³C-NMR (d₆-DMSO, 75 MHz) δ166.78, 164.09, 160.89, 154.39, 146.87,142.46, 140.45, 134.36, 131.49, 130.83, 128.13, 124.41, 117.06, 116.90,126.08.

MS (EI) m/z 282 (M⁺), 172, 116, 89.

HRMS (EI) 282.0804.

EXAMPLE 161 N-(3,4-Difluorophenyl)-8-hydroxy-7-quinolinecarboxamidemonohydrochloride (V-13) (Refer to Chart V)

According to GP II, starting from anhydride U-1 (200 mg), pyridiniumchloride (42 mg), 3,4-difluoroaniline (37 μL) and CHCl₃ (8 mL), amideV-13 is obtained as a light yellow powder (35 mg).

Physical characteristics are as follows:

¹H-NMR (d₆-DMSO, 300 MHz) δ11.20, 8.95, 8.60, 8.05, 7.97, 7.79, 7.45.

¹³C-NMR (d₆-DMSO, 75 MHz) δ166.25, 155.39, 147.45, 140.03, 136.87,136.08, 131.38, 127.75, 124.13, 118.46, 117.20, 116.25, 110.42.

MS (EI) m/z 300 (M⁺), 172, 116, 89

HRMS (EI) 300.0724.

EXAMPLE 162 N-(3,5-Difluorophenyl)-8-hydroxy-7-quinolinecarboxamidemonohydrochloride (V-14) (Refer to Chart V)

According to GP II, starting from anhydride U-1 (200 mg), pyridiniumchloride (42 mg), 3,5-difluoroaniline (48 mg) and CHCl₃ (8 mL), amideV-14 is obtained as a yellow powder (42 mg).

Physical characteristics are as follows:

¹H-NMR (d₆-DMSO, 300 MHz) δ11.60, 8.99, 8.73, 8.07, 7.88, 7.50, 7.50 (m,2H1), 6.97, 6.29.

¹³C-NMR (d₆-DMSO, 300 MHz) δ166.53, 164.48, 161.26, 154.99, 146.85,141.54, 135.64, 131.52, 128.14, 124.27, 116.84, 116.07, 103.62, 99.44.

MS (EI) m/z 300 (M⁺), 172, 129, 116, 102, 89.

HRMS 300.0716.

EXAMPLE 163 8-Hydroxy-N-(4-nitrophenyl)-7quinolinecarboxamide (V-15)(Refer to Chart V)

According to GP IV, starting from ester U-3 (100 mg), 4-nitroaniline (60mg), DIPEA (75 μL) and CH₂Cl₂ (2 mL), stirred for 30 h, then overnightwith MeOH. Amide V-15 appears as a red precipitate that is filtered anddried (10 mg).

Physical characteristics are as follows:

¹H-NMR (d₆-DMSO, 300 MHz) δ8.90, 8.58, 8.25, 7.97, 7.81, 7.33.

MS (EI) m/z 309 (M⁺), 172, 116, 89.

HRMS (EI) 309.0741.

EXAMPLE 164N-[2-Chloro-5-(trifluoromethyl)phenyl]-8-hydroxy-7-quinolinecarboxamide(V-16) (Refer to Chart V)

According to GP IV, starting from ester U-3 (50 mg),2-chloro-5-(trifluoromethyl)aniline (30 μL), DIPEA (40 μL) and CH₂Cl₂ (2mL), stirred for 5 days, then for 6 h with MeOH. The mixture is dilutedin some AcOEt, washed with sat. NaHCO₃/H₂O (1×), with an aq. buffer sol.at pH4 (1×), dried over MgSO₄ and the solvent removed under reducedpressure. Crystallization from AcOEt/hexanes leads to amide V-16 as ayellow powder (26 mg).

Physical characteristics are as follows:

mp: 210-211° C.

¹H-NMR (CD₃OD, 300 MHz) δ10.18, 10.05, 8.38, 8.38, 8.09, 7.79, 7.62.

MS (EI) m/z 366 and 368 (M⁺), 172, 116, 89.

HRMS (EI) 366.0374.

EXAMPLE 165 N-(5-Fluoro-2-methylphenyl)-8-hydroxy-7-quinolinecarboxamide(V-17) (Refer to Chart V)

According to GP IV, starting from ester U-3 (500 mg),5-fluoro-2-methylaniline (0.30 mL), DIPEA (0.30 mL) and CH₂Cl₂ (10 mL),stirred for 24 h, then overnight with MeOH. An orange powderprecipitated, that is filtered and dried under high vacuum. The filtrateis evaporated under reduced pressure, which leads to another fraction oforange precipitate, that is triturated in hot AcOEt/hexanes. Aftercooling to r.t., the orange powder is filtered and dried under highvacuum. Both fractions proves to be amide V-17 (366 mg, 58%).

Physical characteristics are as follows:

mp: 209-210° C.

¹H-NMR (d₆-DMSO, 300 MHz) δ11.95, 8.87, 8.63, 8.25, 8.17, 7.79, 7.27,6.84, 2.36.

¹³C-NMR (d₆DMSO, 75 MHz) δ164.38, 161.99, 158.83, 157.66, 144.94,140.14, 138.77, 136.97, 131.45, 131.07, 128.65, 123.35, 122.63, 115.15,112.53, 109.25, 106.15

MS (EI) m/z 296 (M⁺), 268, 172, 116, 89.

Anal. Found C, 68.67; H, 4.49; N, 9.43.

Also: According to GP V starting with 5-fluoro-2-methylaniline (26 mg).

Physical characteristics are as follows:

MS (ES) m/z P-fraction: Pos. mode: 297 (MH⁺); neg. mode: 295 (M−H⁺).

EXAMPLE 166 N-(2,4-Dimethylphenyl)-8-hydroxy-7-quinolinecarboxamide(V-18) (Refer to Chart V)

According to GP IV, starting from ester U-3 (500 mg),2,4-dimethylaniline (0.27 mL), DIPEA (0.30 mL) and CH₂Cl₂ (10 mL),stirred for 24 h, then overnight with MeOH. After adding some CH₂Cl₂,the sol. is washed with an aq. buffer sol. at pH4 (2×) and sat.NaHCO₃/H₂O (1×). The org. phase is dried over MgSO₄ and the solventremoved under reduced pressure. The residue is triturated inAcOEt/hexanes at r.t. Amide V-18 precipitates as a white powder that isfiltered and dried (378 mg).

Physical characteristics are as follows:

mp: 164-167° C.

¹H-NMR (d₆-DMSO, 300 MHz) δ11.0, 8.90, 8.49, 8.14, 7.96, 7.74, 7.38,7.06, 7.01, 2.29, 2.26.

¹³C-NMR (d₆-DMSO, 75 MHz) δ184.14, 164.49, 156.15, 146.22, 138.04,137.91, 134.28, 133.07, 130.87, 130.74, 128.64, 127.38, 126.64, 123.32,122.18, 114.80, 20.24, 17.71.

MS (EI) m/z 292 (M⁺), 264, 172, 121, 106, 89.

HRMS (EI) 292.1206.

Anal. Found: C, 73.28; H, 5.51; N, 9.50.

Also: According to GP V starting with 2,4-dimethylaniline (25 mg).

Physical characteristics are as follows:

MS (ES) m/z T-fraction: Pos mode: 293 (MH⁺); neg. mode: 291 (M−H⁺).

EXAMPLE 167 8-Hydroxy-N-(3-methylphenyl)-7-quinolinecarboxamide (V-19)(Refer to Chart V)

According to GP IV, starting from ester U-3 (500 mg), 3-methylaniline(0.23 mL), DIPEA (0.30 mL) and CH₂Cl₂ (10 mL), stirred for 24 h, thenovernight with MeOH. After adding some CH₂Cl₂, the sol. is washed withan aq. buffer sol. at pH4 (2×) and sat. NaHCO3/H₂O (1×). The org. phaseis dried over MgSO₄ and the solvent removed under reduced pressure. Theresidue is triturated with AcOEt/hexanes at 40° C. and amide V-19precipitated as a red powder that is filtered and dried under highvacuum (276 mg).

Physical characteristics are as follows:

¹H-NMR (d₆-DMSO, 300 MHz) δ10.90, 8.92, 8.45, 8.03, 7.70, 7.55, 7.41,7.24, 6.94.

¹³C-NMR (d₆-DMSO, 75 MHz) δ165.10, 155.37, 147.65, 138.45, 138.17,137.96, 137.37, 130.61, 128.60, 126.83, 124.39, 123.33, 120.60, 117.29,115.63, 115.29, 21.09.

MS (EI) m/z 278 (M⁺), 172, 116, 107, 89.

HRMS (EI) 278.1049.

Anal. Found: C, 72.95; H, 5.19; N, 9.95.

Also: According to GP V starting with 3-methylaniline (21 mg).

Physical characteristics are as follows:

MS (ES) m/z WU-fraction: Pos mode: 279 (MH⁺); neg. mode: 277 (M−H⁺).

EXAMPLE 168N-(2-Chloro-5-methoxyphenyl)-8-hydroxy-7-quinolinecarboxamide (V-20)(Refer to Chart V)

According to GP IV, starting from ester U-3 (500 mg),2-chloro-5-methoxyaniline hydrochloride (420 mg), DIPEA (0.06 mL) andCH₂Cl₂ (10 mL), are stirred for 6 days, then for 24 h with MeOH. Afteradding some CH₂Cl₂, the sol. is washed with an aq. buffer sol. at pH4(2×) and sat. NaHCO₃/H₂O (1×). The org. phase is dried over MgSO₄ andthe solvent removed under reduced pressure. The residue is trituratedwith AcOEt/hexanes at r.t. and the precipitated grey amide V-20 isfiltered and dried under high vacuum (280 mg).

Physical characteristics are as follows:

¹H-NMR (d₆-DMSO, 300 MHz) δ12.3, 8.85, 8.58, 8.33, 8.17, 7.77, 7.40,7.25, 6.70, 3.76.

¹³C-NMR (d₆-DMSO, 75 MHz) δ184.16, 164.39, 158.28, 145.09, 145.04,139.80, 139.74, 136.80, 131,56, 129.40, 128.66, 123.40, 114.72, 113.58,109.54, 107.31, 55.30.

MS (EI) m/z 328 and 330 (M⁺), 172, 157 and 159, 116, 89.

HRMS (EI) 328.0615.

Anal. Found: C, 61.38; H, 4.17; N, 8.45.

Also: According to GP V starting with 2-chloro-5-methoxyanilinehydrochloride (39 mL) and DIPEA (33 μL).

Physical characteristics are as follows:

MS (ES) m/z T-fraction: Pos. mode: 329 and 331 (MH⁺); neg. mode: 327 and329 (M−H⁺).

EXAMPLE 169 8-Hydroxy-N-naphth-2-yl-7-quinolinecarboxamidemonohydrochloride (V-21) (Refer to Chart V)

Following GP III starting from 2-aminonaphthalene (29 mg).

Physical characteristics are as follows:

MS (ES) m/z Pos. mode: 315 (MH⁺); neg. mode: 313 (M−H⁺).

EXAMPLE 1708-Hydroxy-N-{4-[(indazo-6-ylamino)sulfonyl]phenyl}-7-quinolinecarboxamidemonohydrochloride (V-22) (Refer to Chart V)

Following GP III starting with N¹-indazo-6-ylsulfanilamide (60 mg).

Physical characteristics are as follows:

MS (ES) m/z: Pos. mode 460 (MH⁺); neg. mode: 458 (M−H⁺). Contaminatedwith sulfanilamide.

EXAMPLE 171 N-(3-Bromophenyl)-8-hydroxy-7-quinolinecarboxamidemonohydrochloride (V-23) (Refer to Chart V)

Following GP III starting from 3-bromoaniline (22 μL).

Physical characteristics are as follows:

MS (ES) m/z Pos. mode: 343, 345 (MH⁺); neg. mode: 341, 343 (M−H⁺).

EXAMPLE 172 N-(3,4-Dichlorophenyl)-8-hydroxy-7-quinolinecarboxamidemonohydrochloride (V-24) (Refer to Chart V)

Following GP III starting from 3,4-dichloroaniline (33 mg).

Physical characteristics are as follows:

MS (ES) m/z Pos. mode: 333, 335, 337 (MH⁺); neg. mode: 331, 333, 335(M−H⁺). Contaminated with carbamate.

EXAMPLE 173 N-(3,5-Dichlorophenyl)-8-hydroxy-7-quinolinecarboxamidemonohydrochloride (V-25) (Refer to Chart V)

Following GP III starting from 3,5-dichloroaniline (33 mg).

Physical characteristics are as follows:

MS (ES) m/z Pos. mode: 333, 335, 337 (MH⁺); neg. mode: 331, 333, 335(M−H⁺).

EXAMPLE 174 8-Hydroxy-N-(3-iodophenyl)-7-quinolinecarboxamidemonohydrochloride (V-26) (Refer to Chart V)

Following GP III starting from 3-iodoaniline (44 mg).

Physical characteristics are as follows:

MS (ES) m/z Pos. mode: 391 (MH⁺); neg. mode: 389 (M−H⁺).

EXAMPLE 175 N-(3-Benzoxyphenyl)-8-hydroxy-7-quinolinecarboxamidemonohydrochloride (V-27) (Refer to Chart V)

Following GP III starting from 3-benzoxyaniline (40 mg).

Physical characteristics are as follows:

MS (ES) m/z Pos. mode: 371 (MH⁺); neg. mode: 369 (M−H⁺).

EXAMPLE 1768-Hydroxy-N-[3-(methylmercapto)phenyl]-7-quinolinecarboxamidemonohydrochloride (V-28) (Refer to Chart V)

Following GP III starting from 3-(methylmercapto)aniline (25 μL).

Physical characteristics are as follows:

MS (ES) m/z Pos. mode: 311 (MH⁺); neg. mode: 309 (M−H⁺).

EXAMPLE 177 N-(3,5-Dimethylphenyl)-8-hydroxy-7-quinolinecarboxamidemonohydrochloride (V-29) (Refer to Chart V)

Following GP III starting from 3,5-dimethylaniline (25 μL).

MS (ES) m/z: Pos. mode: 293 (MH⁺); neg. mode: 291 (M−H⁺).

EXAMPLE 178 N-(4-Bromophenyl)-8-hydroxy-7-quinolinecarboxamidemonohydrochloride (V-30) (Refer to Chart V)

Following GP III starting from 4-bromoaniline (35 mg).

Physical characteristics are as follows:

MS (ES) m/z Pos. mode: 343, 345 (MH⁺); neg. mode: 341, 343 (M−H⁺).Contaminated with carbamate.

EXAMPLE 179 8-Hydroxy-N-(4-phenoxyphenyl)-7-quinolinecarboxamidemonohydrochloride (V-31) (Refer to Chart V)

Following GP III starting from 4-phenoxyaniline (37 mg).

Physical characteristics are as follows:

MS (ES) m/z Pos. mode: 357 (MH⁺); neg. mode: 355 (M−H⁺).

EXAMPLE 180N-(3,5-Dichloro-4-hydroxyphenyl)-8-hydroxy-7-quinolinecarboxamidemonohydrochloride (V-32) (Refer to Chart V)

Following GP III starting from 3,5-dichloro-4-hydroxyaniline (36 mg).

MS (ES) m/z: Pos. mode: 349, 351, 353 (NM⁺); neg. mode: 347, 349, 351(M−H⁺).

EXAMPLE 181 8-Hydroxy-N-biphen-4-yl-7-quinolinecarboxamidemonohydrochloride (V-33) (Refer to Chart V)

Following GP III starting from 4-aminobiphenyl (34 mg).

Physical characteristics are as follows:

MS (ES) m/z Pos. mode: 341 (MH⁺); neg. mode: 339 (M−H⁺).

EXAMPLE 1828-Hydroxy-N-[4-(4-nitrophenylmercapto)phenyl]-7-quinolinecarboxamidemonohydrochloride (V-34) (Refer to Chart V)

Following GP III starting from 4-(4-nitrophenylmercapto)aniline (49 mg).

Physical characteristics are as follows:

MS (ES) m/z Pos. mode: 418 (MH⁺); neg. mode: 416 (M−H⁺).

EXAMPLE 183 N-(4-Benzoxyphenyl)-8-hydroxy-7-quinolinecarboxamidemonohydrochloride (V-35) (Refer to Chart V)

Following GP III starting from 4-benzoxyaniline (47 mg).

Physical characteristics are as follows:

MS (ES) m/z Pos. mode: 371 (MH⁺); neg. mode: 369 (M−H⁺).

EXAMPLE 1848-Hydroxy-N-[4-(4-nitrophenoxy)phenyl]-7-quinolinecarboxamidemonohydrochloride (V-36) (Refer to Chart V)

Following GP III starting from 4-(4-nitrophenoxy)aniline (46 mg).

Physical characteristics are as follows:

MS (ES) m/z Pos. mode: 402 (MH⁺); neg. mode: 400 (M−H⁺).

EXAMPLE 185 N-(4-cyclohexylphenyl)-8-hydroxy-7-quinolinecarboxamidemonohydrochloride (V-37) (Refer to Chart V)

Following GP V starting from 4-cyclohexylaniline (35 mg).

Physical characteristics are as follows:

MS (ES) m/z Pos. mode: 347 (MH⁺); neg. mode: 345 (M−H⁺).

EXAMPLE 186 8-Hydroxy-N-naphth-1-yl-7-quinolinecarboxamide (V-38) (Referto Chart V)

Following GP V starting from 1-aminonaphthalene (29 mg).

Physical characteristics are as follows:

MS (ES) m/z T-fraction: Pos. mode: 315 (MH⁺); neg. mode: 313 (M−H⁺).

EXAMPLE 187 8N-(4-Bromonaphth-1-yl)-8-hydroxy-7-quinolinecarboxamide(V-39) (Refer to Chart V)

Following GP V starting from 1-amino-4-bromonaphthalene (44 mg).

Physical characteristics are as follows:

MS (ES) m/z P-fraction: Neg. mode: 391 and 393 (M−H⁺).

EXAMPLE 188 8-Hydroxy-N-(2-pyrrol-1-ylphenyl)-7-quinolinecarboxamide(V-40) (Refer to Chart V)

Following GP V starting from 1-(2-aminophenyl)pyrrole (32 mg).

Physical characteristics are as follows:

MS (ES) m/z T-fraction: Pos. mode: 330 (MH⁺); neg. mode: 328 (M−H⁺).

EXAMPLE 189 8-Hydroxy-N-indol-5-yl-7-quinolinecarboxamide (V-41) (Referto Chart V)

Following GP V starting from 5-aminoindole (26 mg).

Physical characteristics are as follows:

MS (ES) m/z P- and WU-fractions: Pos. mode: 304 (MH⁺); neg. mode: 302(M−H⁺).

EXAMPLE 190N-Benzo-2,1,3-thiadiazol-4-yl-8-hydroxy-7-quinolinecarboxamide (V-42)(Refer to Chart V)

Following GP V starting from 4-aminobenzo-2,1,3-thiadiazole (30 mg).

Physical characteristics are as follows:

MS (ES) m/z P-fraction: neg. mode: 302 (M−H⁺).

EXAMPLE 191 8-Hydroxy-N-quinolin-5-yl-7-quinolinecarboxamide (V-43)(Refer to Chart V)

Following GP V starting from 5-aminoquinoline (29 mg).

Physical characteristics are as follows:

MS (ES) m/z P- and WU-fractions: Pos. mode: 316 (MH⁺) and 338 (MNa⁺);neg. mode: 314 (M−H⁺).

EXAMPLE 192 8-Hydroxy-N-quinolin-8-yl-7-quinolinecarboxamide (V-44)(Refer to Chart V)

Following GP V starting from 8-aminoquinoline (29 mg).

Physical characteristics are as follows:

MS (ES) m/z P-fraction: Pos. mode: 316 (MH⁺); neg. mode: 314 (M−H⁺).

EXAMPLE 193 8-Hydroxy-N-isoquinolin-5-yl-7-quinolinecarboxamide (V-45)(Refer to Chart V)

Following GP V starting from 5-aminoisoquinoline (29 mg).

Physical characteristics are as follows:

MS (ES) m/z P-fraction: Pos. mode: 316 (MH⁺); neg. mode: 314 (M−H⁺).

EXAMPLE 194 8-Hydroxy-N-(4-methoxy-2-nitrophenyl)-7-quinolinecarboxamide(V-46) (Refer to Chart V)

Following GP V starting from 4-methoxy-2-nitroaniline (34 mg).

Physical characteristics are as follows:

MS (ES) m/z P-fraction: Neg. mode: 338 (M−H⁺). Contaminated withquinoline methyl ester.

EXAMPLE 1958-Hydroxy-N-[2-nitro-4-(trifluoromethyl)phenyl]-7-quinolinecarboxamide(V-47) (Refer to Chart V)

Following GP V starting from 2-nitro-4-(trifluoromethyl)aniline (41 mg).

Physical characteristics are as follows:

MS (ES) m/z P-fraction: Pos mode: 378 (MH⁺); neg. mode: 338 (M−H⁺).

EXAMPLE 196 N-(3,5-Dinitrophenyl)-8-hydroxy-7-quinolinecarboxamide(V-48) (Refer to Chart V)

Following GP V starting from 3,5-dinitroaniline (37 mg).

Physical characteristics are as follows:

MS (ES) m/z: P-fraction: Neg. mode 353 (M−H⁺).

EXAMPLE 1978-Hydroxy-N-[4-nitro-2-(trifluoromethyl)phenyl]-7-quinolinecarboxamide(V-49) (Refer to Chart V)

Following GP V starting from 4-nitro-2-(trifluoromethyl)aniline (41 mg).

Physical characteristics are as follows:

MS (ES) m/z: P-fraction Pos. mode: 378 (MH⁺), 400 (MNa⁺); neg. mode: 376(M−H⁺).

EXAMPLE 198 N-(2-Cyanophenyl)-8-hydroxy-7-quinolinecarboxamide (V-50)(Refer to Chart V)

Following GP V starting from 2-aminobenzonitrile (24 mg).

Physical characteristics are as follows:

MS (ES) m/z P-fraction: Pos. mode: 290 (MH+), 312 (MNa⁺); neg. mode: 388(M−H⁺).

EXAMPLE 199 N-(2-Bromophenyl)-8-hydroxy-7-quinolinecarboxamide (V-51)(Refer to Chart V)

Following GP V starting from 2-bromoaniline (35 mg).

Physical characteristics are as follows:

MS (ES) m/z T-fraction: Pos. mode: 343 and 345 (MH⁺); neg. mode: 341 and343 (M−H⁺).

EXAMPLE 200 N-(2,4-Dibromophenyl)-8-hydroxy-7-quinolinecarboxamide(V-52) (Refer to Chart V)

Following GP V starting from 2,4-dibromoaniline (50 mg).

Physical characteristics are as follows:

MS (ES) m/z P-fraction: Neg. mode: 419, 421 and 423 (M−H⁺). Contaminatedwith 8-hydroxy-7-quinoline carboxylic acid.

EXAMPLE 201 N-(2,5-Dibromophenyl)-8-hydroxy-7-quinolinecarboxamide(V-53) (Refer to Chart V)

Following GP V starting from 2,5-dibromoaniline (50 mg).

Physical characteristics are as follows:

MS (ES) m/z P-fraction: Pos. mode: 421, 423 and 425 (MH⁺); neg. mode:419, 421 and 423 (M−H⁺).

EXAMPLE 202 N-(2-Fluorophenyl)-8-hydroxy-7-quinolinecarboxamide (V-54)(Refer to Chart V)

Following GP V starting from 2-fluoroaniline (22 mg).

Physical characteristics are as follows:

MS (ES) m/z P-fraction: Pos. mode: 283 (MH⁺), 305 (MNa⁺); neg. mode: 281(M−H⁺).

EXAMPLE 203N-(4-Cyano-2,3,5,6-tetrafluorophenyl)-8-hydroxy-7-quinolinecarboxamide(V-55) (Refer to Chart V)

Following GP V starting from 4-amino-2,3,5,6-tetrafluorobenzonitrile (38mg).

Physical characteristics are as follows:

MS (ES) m/z T-fraction: Pos. mode: 362 (MH⁺); neg. mode: 260 (M−H⁺).

EXAMPLE 204 N-(2,4-Difluorophenyl)-8-hydroxy-7-quinolinecarboxamide(V-56) (Refer to Chart V)

Following GP V starting from 2,4-difluoroaniline (26 mg).

Physical characteristics are as follows:

MS (ES) m/z P-fraction: Pos. mode: 301 (MH⁺), 323 (MNa⁺); neg. mode: 299(M−H⁺).

EXAMPLE 205 8-Hydroxy-N-(2,4,5-trifluorophenyl)-7-quinolinecarboxamide(V-57) (Refer to Chart V)

Following GP V starting from 2,4,5-trifluoroaniline (30 mg).

Physical characteristics are as follows:

MS (ES) m/z T-fraction: Pos. mode: 319 (MH⁺); neg. mode: 317 (M−H⁺).

EXAMPLE 206 N-(2-Chlorophenyl)-8-hydroxy-7-quinolinecarboxamide (V-58)(Refer to Chart V)

Following GP V starting from 2-chloroaniline (26 mg).

Physical characteristics are as follows:

MS (ES) m/z T-fraction: Pos. mode: 299 and 301 (MH⁺); neg. mode: 297 and299 (M−H⁺). Contaminated with quinoline methyl ester.

EXAMPLE 207 N-(4-Bromo-2-chlorophenyl)-8-hydroxy-7-quinolinecarboxamide(V-59) (Refer to Chart V)

Following GP V starting from 4-bromo-2-chloroaniline (42 mg).

Physical characteristics are as follows:

MS (ES) m/z P-fraction: Pos. mode: 377, 379 and 381 (MH⁺); neg. mode:375, 377 and 379 (M−H⁺).

EXAMPLE 208 N-(2,4-Dichlorophenyl)-8-hydroxy-7-quinolinecarboxamide(V-60) (Refer to Chart V)

Following GP V starting from 2,4-dichloroaniline (32 mg).

Physical characteristics are as follows:

MS (ES) m/z P-fraction: Pos. mode: 333, 335 and 337 (MH⁺); neg. mode:331, 333 and 335 (M−H⁺).

EXAMPLE 209 N-(2-Chloro-4-nitrophenyl)-8-hydroxy-7-quinolinecarboxamide(V-61) (Refer to Chart V)

Following GP V starting with 2-chloro-4-nitroaniline (35 mg).

Physical characteristics are as follows:

MS (ES) m/z P-fraction: Neg. mode: 342 and 344 (M−H⁺).

EXAMPLE 210 N-(2,5-Dichlorophenyl)-8-hydroxy-7-quinolinecarboxamide(V-62) (Refer to Chart V)

Following GP V starting from 2,5-dichloroaniline (33 mg).

Physical characteristics are as follows:

MS (ES) m/z P-fraction Pos. mode: 333, 335 and 337 (MH⁺); neg. mode:331, 333 and 335 (M−H⁺).

EXAMPLE 211 N-(2-Chloro-5-methylphenyl)-8-hydroxy-7-quinolinecarboxamide(V-63) (Refer to Chart V)

Following GP V starting from 2-chloro-5-methylaniline (29 mg).

Physical characteristics are as follows:

MS (ES) m/z T-fraction: Pos. mode: 313 and 315 (MH⁺); neg. mode: 311 and313 (M−H⁺).

EXAMPLE 212 8-Hydroxy-N-(2-iodophenyl)-7-quinolinecarboxamide (V-64)(Refer to Chart V)

Following GP V starting from 2-iodoaniline (44 mg).

Physical characteristics are as follows:

MS (ES) m/z T-fraction: Pos. mode: 391 (MH⁺); neg. mode: 389 (M−H⁺).Contaminated with quinoline methyl ester.

EXAMPLE 213 8-Hydroxy-N-(2-nitrophenyl)-7-quinolinecarboxamide (V-65)(Refer to Chart V)

Following GP V starting from 2-nitroaniline (28 mg).

Physical characteristics are as follows:

MS (ES) m/z T-fraction: Neg. mode: 308 (M−H⁺), 331 (MNa−H⁺).Contaminated with quinoline methyl ester.

EXAMPLE 214N-(5-Chloro-2-hydroxyphenyl)-8-hydroxy-7-quinolinecarboxamide (V-66)(Refer to Chart V)

Following GP V starting from 5-chloro-2-hydroxyaniline (29 mg).

Physical characteristics are as follows:

MS (ES) m/z P-fraction: Pos. mode: 357 and 359 (MH⁺), 379 and 381(MNa⁺); neg. mode: 355 and 357 (M−H⁺).

EXAMPLE 215 8-Hydroxy-N-(2-hydroxy-5-nitrophenyl)-7-quinolinecarboxamide(V-67) (Refer to Chart V)

Following GP V starting from 2-hydroxy-5-nitroaniline (31 mg).

Physical characteristics are as follows:

MS (ES) m/z P-fraction: Neg. mode: 324 (M−H⁺).

EXAMPLE 2168-Hydroxy-N-(2-hydroxy-5-methylphenyl)-7-quinolinecarboxamide (V-68S)(Refer to Chart V)

Following GP V starting from 2-hydroxy-5-methylaniline (25 mg).

Physical characteristics are as follows:

MS (ES) m/z WU-fraction: Pos. mode: 295 (MH⁺); neg. mode: 293 (M−H⁺).

EXAMPLE 217 N-Biphen-2-yl-8-hydroxy-7-quinolinecarboxamide (V-69) (Referto Chart V)

Following GP V starting from 2-aminobiphenyl (34 mg).

Physical characteristics are as follows:

MS (ES) m/z T-fraction: Pos. mode: 341 (MH⁺); neg. mode: 339 (M−H⁺).

EXAMPLE 2188-Hydroxy-N-[2-(methylmercapto)phenyl]-7-quinolinecarboxamide (V-70)(Refer to Chart V)

Following GP V starting from 2-methylmercaptoaniline (28 mg).

Physical characteristics are as follows:

MS (ES) m/z T-fraction: Pos. mode: 311 (MH⁺); neg. mode: 309 (M−H⁺).

EXAMPLE 2198-Hydroxy-N-[2-(trifluoromethyl)phenyl]-7-quinolinecarboxamide (V-71)(Refer to Chart V)

Following GP V starting from 2-(trifluoromethyl)aniline (33 mg).

Physical characteristics are as follows:

MS (ES) m/z T-fraction: Neg. mode: 331 (M−H⁺). Contaminated withquinoline methyl ester.

EXAMPLE 220 8-Hydroxy-N-(2-methylphenyl)-7-quinolinecarboxamide (V-72)(Refer to Chart V)

Following GP V starting from 2-methylaniline (22 mg).

Physical characteristics are as follows:

MS (ES) m/z T-fraction: Pos. mode: 279 (MH⁺); neg. mode: 277 (M−H⁺).

EXAMPLE 221 8-Hydroxy-N-(2-methyl-3-nitrophenyl)-7-quinolinecarboxamide(V-73) (Refer to Chart V)

Following GP V starting with 2-methyl-3-nitroaniline (31 mg).

Physical characteristics are as follows:

MS (ES) m/z T-fraction: Pos. mode: 324 (MH⁺); neg. mode: 322 (M−H⁺).

EXAMPLE 222 N-(2,3-Dimethylphenyl)-8-hydroxy-7-quinolinecarboxamide (V-74) (Refer to Chart V)

Following GP V starting with 2,3-dimethylaniline (25 mg).

Physical characteristics are as follows:

MS (ES) m/z T-fraction: Pos. mode: 293 (MH⁺); neg. mode: 291 (M−H⁺).

EXAMPLE 223 8-Hydroxy-N-(2,4,6-trimethylphenyl)-7-quinolinecarboxamide(V-75) (Refer to Chart V)

Following GP V starting from 2,4,6-trimethylaniline (25 mg).

Physical characteristics are as follows:

MS (ES) m/z T- and WU-fractions: Pos. mode: 307 (MH⁺); neg. mode: 305(M−H⁺).

EXAMPLE 224 N-(2-Ethylphenyl)-8-hydroxy-7-quinolinecarboxamide (V-76)(Refer to Chart V)

Following GP V starting with 2-ethylaniline (25 mg).

Physical characteristics are as follows:

MS (ES) m/z T-fraction: Pos. mode: 293 (MH⁺); neg. mode: 291 (M−H⁺).

EXAMPLE 2258-Hydroxy-N-[3-(trifluoromethyl)phenyl]-7-quinolinecarboxamide (V-77)(Refer to Chart V)

Following GP V starting with 3-(trifluoromethyl)aniline (32 mg).

Physical characteristics are as follows:

MS (ES) m/z T-fraction: Pos. mode: 333 (MH⁺); neg. mode: 231 (M−H⁺).

EXAMPLE 226 8-Hydroxy-N-(2-methyl-4-fluorophenyl)-7-quinolinecarboxamide(V-78) (Refer to Chart V)

Following GP V starting with 2-methyl-4-fluoroaniline (25 mg).

Physical characteristics are as follows:

MS (ES) m/z T-fraction: Pos. mode: 297 (MH⁺); neg. mode: 295 (M−H⁺).

EXAMPLE 227 N-(4-Chloro-2-methylphenyl)-8-hydroxy-7-quinolinecarboxamide(V-79) (Refer to Chart V)

Following GP V starting with 2-chloro-2-methylaniline (29 mg).

Physical characteristics are as follows:

MS (ES) m/z P-fraction: Pos. mode: 313 and 315 (MH⁺), 335 and 335(MNa⁺); neg. mode: 311 and 313 (M−H⁺).

EXAMPLE 228N-(4-Chloro-2-methoxy-5-methylphenyl)-8-hydroxy-7-quinolinecarboxamide(V-80) (Refer to Chart V)

Following GP V starting with 4-chloro-2-methoxy-5-methylaniline (55 mg).

Physical characteristics are as follows:

MS (ES) m/z T-fraction: Pos. mode: 343 and 345 (MH⁺); neg. mode: 341 and343 (M−H⁺).

EXAMPLE 229 N-(4-tert-Butylphenyl)-8-hydroxy-7-quinolinecarboxamide(V-81) (Refer to Chart V)

Following GP V starting with 4-tert-butylaniline (31 mg).

Physical characteristics are as follows:

MS (ES) m/z T-fraction: Pos. mode: 321 (MH⁺); neg. mode: 319 (M−H⁺).

EXAMPLE 230 8-Hydroxy-N-(4-propylphenyl)-7-quinolinecarboxamide (V-82)(Refer to Chart V)

Following GP V starting with 4-propylaniline (28 mg).

Physical characteristics are as follows:

MS (ES) m/z T-fraction: Pos. mode: 307 (MH⁺); neg. mode: 305 (M−H⁺).

EXAMPLE 231 N-(2,6-Di-i-propylphenyl)-8-hydroxy-7-quinolinecarboxamide(V-83) (Refer to Chart V)

Following GP V starting from 2,6-di-i-propylaniline (36 mg).

Physical characteristics are as follows:

MS (ES) m/z T-fraction: Neg. mode: 347 (M−H⁺).

EXAMPLE 232 N-(4-Bromo-2-fluorophenyl)-8-hydroxy-7-quinolinecarboxamide(V-84) (Refer to Chart V)

Following GP V starting from 4-bromo-2-fluoroaniline (31 mg).

Physical characteristics are as follows:

MS (ES) m/z T- and P-fractions: Pos. mode: 361 and 363 (MH⁺); neg. mode:359 and 361 (M−H⁺).

EXAMPLE 233 8-Hydroxy-N-(2,3,4-trifluorophenyl)-7-quinolinecarboxamide(V-85) (Refer to Chart V)

Following GP V starting from 2,3,4-trifluoroaniline (30 mg).

Physical characteristics are as follows:

MS (ES) m/z P-fraction: Pos. mode: 319 (MH⁺), 341 (MNa⁺); neg. mode: 317(M−H⁺).

EXAMPLE 234 N-(2-Fluoro-4-iodophenyl)-8-hydroxy-7-quinolinecarboxamide(V-86) (Refer to Chart V)

Following GP V starting from 2-fluoro-4-iodoaniline (48 mg).

Physical characteristics are as follows:

MS (ES) m/z T- and P-fractions: Pos. mode: 409 (MH⁺); neg. mode: 407(M−H⁺).

EXAMPLE 235 8-Hydroxy-N-[4-(hydroxymethyl)phenyl]-7-quinolinecarboxamide(V-87) (Refer to Chart V)

Following GP V starting from 4-(hydroxymethyl)aniline (29 mg).

Physical characteristics are as follows:

MS (ES) m/z P-fraction: Pos. mode: 295 (MH⁺); neg. mode: 293 (M−H⁺).

EXAMPLE 236 N-Benzo-1,3-thiazol-6-yl-8-hydroxy-7-quinolinecarboxamide(V-88) (Refer to Chart V)

Following GP V starting from 6-amino-benzo-1,3-thiazole (31 mg).

Physical characteristics are as follows:

MS (ES) m/z P-fraction: Pos. mode: 322 (MH⁺); neg. mode: 320 (M−H⁺).

EXAMPLE 237 8-Hydroxy-N-indazol-5-yl-7-quinolinecarboxamide (V-89)(Refer to Chart V)

Following GP V starting from 5-aminoindazole (27 mg).

Physical characteristics are as follows:

MS (ES) m/z P-fraction: Neg. mode: 303 (M−H⁺).

EXAMPLE 2388-Hydroxy-N-[2-methoxy-5-(trifluoromethyl)phenyl]-7-quinolinecarboxamide(V-90) (Refer to Chart V)

Following GP V starting from 2-methoxy-5-(trifluoromethyl)aniline (39mg).

Physical characteristics are as follows:

MS (ES) m/z T-fraction: Pos. mode: 363 (MH⁺); neg. mode: 361 (M−H⁺).

EXAMPLE 239 8-Hydroxy-N-(5-iodo-2-methylphenyl)-7-quinolinecarboxamide(V-91) (Refer to Chart V)

Following GP V starting with 5-iodo-2-methylaniline (47 mg).

Physical characteristics are as follows:

MS (ES) m/z T- and P-fractions: Pos. mode: 405 (MH+); neg. mode: 403(M−H⁺).

EXAMPLE 240 N-(2-Chloro-4-cyanophenyl)-8-hydroxy-7-quinolinecarboxamide(V-92) (Refer to Chart V)

Following GP V starting with 4-amino-3-chlorobenzonitrile (31 mg).

Physical characteristics are as follows:

MS (ES) m/z T-fraction: Neg. mode: 322 and 324 (M−H⁺).

EXAMPLE 241 N-(5-Bromopyridin-2-yl)-8-hydroxy-7-quinolinecarboxamide(V-93) (Refer to Chart V)

Following GP V starting with 2-amino-5-bromopyridine (35 mg).

Physical characteristics are as follows:

MS (ES) m/z P-fraction: Pos. mode: 344 and 342 (MH⁺); neg. mode: 340 and342 (M−H⁺).

EXAMPLE 242 8-Hydroxy-N-(8-hydroxyquinolin-2-yl)-7-quinolinecarboxamide(V-94) (Refer to Chart V)

Following GP V starting with 2-amino-8-hydroxyquinoline (33 mg).

Physical characteristics are as follows:

MS (ES) m/z T- and P-fractions: Pos. mode: 332 (MH⁺); neg. mode: 330(M−H⁺).

Preparation 38 2-Amino-5-alkylamino-1,3,4-thiadiazoles (GP I) (Refer toChart W.)

2-Amino-5-bromo-1,3,4-thiadiazole W-95 (1 eq.) is dissolved in DMF atr.t. The alkyl amine (about 1 eq.) and DIPEA (1-3 eq.) are addedrespectively and the solution stirred for 20 h. The solvent is removedunder reduced pressure, the residue is diluted in AcOEt and washed withan aq. buffer sol. at pH 4 (2×). The org. phase is dried over MgSO₄,filtered, and the solvent removed under reduced pressure. The residue iseither crystallized from AcOEt/hexanes or purified by FC.

Preparation 39 N-Aryl-8-hydroxy-7-quinolinecarboxamides from anhydrideU-1, procedure for single compounds (GP II):

Anhydride U-1 (1 eq.) is dissolved in CHCl₃ (n mL) at r.t. Pyridiniumchloride (1 eq) and then the arylamine (about 1 eq.) are added. Thesolution is stirred for 6 h at r.t. 1M HCl/H₂O (n mL) is added and thebiphasic mixture is stirred efficiently overnight. The precipitate isfiltered, washed with a little water and CH₂Cl₂ and dried under highvacuum.

Preparation 40 N-Aryl-8-hydroxy-7-quinolinecarboxamides from anhydrideU-1, procedure for parallel synthesis (GP III)

The aryl amines (0.20 mmol) are laid into syringes corked at theiroutput and set with a frit at the bottom of their large section. A sol.of anhydride U-1 (0.1M) and of pyridinium chloride (0.1M) in CHCl₃ isprepared. This solution (2 mL/syringe) is added into the syringes; ifthe arylamine is a liquid, it is added at this stage only; if thearylamine is a hydrochloride salt, DIPEA (33 ,μL, 1 eq) is added. Thesyringes are tightly closed at their bottoms and shaken for 6 h at r.t.1M HCl/H₂O (2 mL) is added and the biphasic mixture is shakenefficiently overnight. The precipitate is isolated by sucking thesolvent from the bottom of the syringes, is washed with a little waterand CH₂Cl₂ and dried under high vacuum.

Preparation 41 N-Aryl-8-hydroxy-7-quinolinecarboxamides from the esterU-3, procedure for single compounds (GP IV)

Ester U-3 is dissolved in CH₂Cl₂ and the arylamine (about 1 eq) andDIPEA (about 1 eq.) are added. The reaction mixture is stirred between 6h and 6 days. MeOH (same amount as CH₂Cl₂) is added and the mixture isstirred between 6 h and 18 h. For the work-up procedures, see specificexamples below.

Preparation 42 N-Aryl-8-hydroxy-7-quinolinecarboxamides from ester U-3,procedure for parallel synthesis (GP V)

The aryl amines (0.2 mmol) are put into syringes corked at their outputand set with a frit at the bottom of their large section. A sol. ofester U-3 (0.05M) and of DIPEA (0.05M) in CH₂Cl₂ is prepared and addedto the arylamines (4 mL for each amine); if the arylamine is a liquid,it is added at this stage only; if the arylamine is a salt, DIPEA (33μL, 1 eq) is added. The syringes are tightly closed and shaken for days.MeOH (2-4 mL) is added and the mixture is shaken for 6 h. Theprecipitate, if any, is isolated by sucking the solvent from the bottomof the syringes, washed with AcOEt and dried under high vacuum(P-fraction). The filtrate is washed with sat. NaHCO/H₂O (1×) and an aq.buffer sol. at pH4 (1×); each time, the aq. phase is pipetted out of theseringe. If a precipitate appeared during the work-up, it is filteredand dried (WU-fraction). The filtrate is blown down with a nitrogenstream, AcOEt (4 mL) is added and the mixture heated to 65° C. for 30min. and cooled to 0° C. The solvent is pipetted out and the residuedried under high vacuum (T-fraction). The org. phase is blown down andthe residue dried under high vacuum as well (S-fraction). The degree ofhydration of the obtained products was not determined.

Preparation 43 Hydrolysis of the tert-butyl esters to the carboxylicacids (GP VI)

tert-Butyl ester is dissolved in TFA at 0° C. and the solution stirredfor 4 h at r.t. The solvent is removed under reduced pressure and theresidue triturated in hot EtOH (95%). After cooling down to r.t. or 0°C., the precipitated is filtered, washed with AcOEt and dried under highvacuum.

Preparation 448-{[(2,2,2-Trichloroethoxy)carbonyl]oxy}-7-quinolinecarboxylic acidanhydride with 2,2,2-trichloroethyl hydrogen carbonate (U-1)

In a flame-dried flask, 8-hydroxy-7-quinolinecarboxylic acid (2.00 g) issuspended into CH₂Cl₂ (100 mL) and DIPEA (3.70 mL) is added. The mixtureis stirred until homogeneity is reached and cooled to 0C. Trichloroethylchloroformate (3.00 mL) is added and the solution is stirred for 3 h at0° C., then stirred for another hour while allowed to warm up slowly tor.t. The solution is washed with 1M HCl/H₂O (1×), dried over Na₂CO₃ andthe solvent removed under reduced pressure. Crystallization of theresidue from CHCl₃/hexanes yields the desired product (5.20 g).

Physical characteristics are as follows:

mp: 133-4° C.

¹H-NMR (CDCl₃, 300 MHz) δ9.05, 8.26, 8.11, 7.88, 7.61, 4.97, 4.95.

¹³C-NMR (CDCl₃, 75 MHz) δ: 157.56, 152.13, 151.59, 149.25, 147.71,141.09, 135.82, 132.64, 126.57, 126.45, 124.44, 119.67, 93.96, 93.42.

MS (FAB) m/z 538, 540 and 542 (MH⁺), 172.

HRMS (FAB): found: 537.8609.

Anal. Found: C, 35.12; H, 1.85; N, 2.65.

Preparation 45 8-Acetoxy-7-quinolinecarboxylic acid (U-2)

This compound is prepared according to literature procedure. (GermanPatent No. 540842, Dec. 10, 1931.)

Physical characteristics are as follows:

¹H-NMR (d₆-DMSO, 300 MHz) δ13.35, 8.99, 8.46, 8.00, 7.95, 7.67, 2.38.

¹³C-NMR (d₆-DMSO, 75 MHz) δ172.46, 169.22, 166.21, 152.08, 147.95,141.42, 136.61, 131.35, 127.08, 126.13, 124.07, 21.20.

Preparation 46 7-(Fluorocarbonyl)-quinolin-8-yl acetate (U-3)

In a flame-dried flask under Ar, 8-acetoxy-7-quinolinecarboxylic acidU-2 (4.30 g) is suspended into CH₂Cl₂ (110 mL). Pyridine (1.50 mL) isadded and the suspension cooled to −40° C. Cyanuric fluoride (3.00 mL)is added and the mixture stirred for 3 h, while the temperature roseslowly to 0° C. Ice and water and CH₂Cl₂ (100 mL) were added. Phaseswere shaken, separated and the aq. phase extracted with CH₂Cl₂ (1×). Thecombined org. phases were dried over MgSO₄, filtered, and the solvent isremoved under reduced pressure. Crystallization of the residue fromhexanes yields ester U-3 as white needles (4.10 g).

Physical characteristics are as follows:

mp: 130-132° C.

¹H-NMR (CDCl₃, 300 MHz) δ9.05, 8.22, 8.02, 7.80, 7.58, 2.58.

¹³C-NMR (CDCl₃, 75 MHz) δ169.06, 156.59, 151.89, 141.42, 136.07, 132.92,126.77, 126.03, 124.41, 118.10, 117.30, 20.88.

MS (FAB) m/z 234 (MH⁺), 192, 172.

HRMS (FAB): 234.0569.

Anal. C, 60.98; H, 3.55; N, 6.24.

Preparation 47 2-Amino-5-bromo-1,3,4-thiadiazole (W-95) (Refer to ChartW.)

To a stirred sol. of 2-amino-1,3,4-thiadiazole (40.5 g) in acetic acid(250 mL) is added bromine (22.7 ml) over about 20 minutes. The flask issurrounded by an ice bath during the addition to maintain the reactiontemperature near 25° C. Following the addition, the ice bath is removedand the clear red sol. stirred at r.t. for 18 hours, then added to 1 Lof cracked ice. Excess bromine is quenched with 10% NaHSO₃/H₂O and 40 mlof 50% NaOH/H₂O is added. The precipitated solid is isolated byfiltration and washed well with water, then dissolved in 300 ml of watercontaining 40 ml conc. HCl. The solution is filtered from a small amountof solid, then 87 g of K₂HPO₄ in a small quantity of water is added. Theresulting slurry is chilled in ice and filtered, and the solid washedwell with water. Recrystallization of the product from 400 ml of ethanolprovides thiadiazole W-95 (26.3 g) as tan crystals.

Physical characteristics are as follows:

¹H-NMR (d₆-DMSO) δ7.51.

Preparation 48 2-Amino-5-(2-phenylethyl)amino-1,3,4-thiadiazole (W-96)(Refer to Chart W.)

A mixture of 2-amino-5-bromo-1,3,4-thiadiazole W-95 (360 mg), ofphenethylamine (0.38 mL) and of K₂HPO₄ (522 mg) in DMF (2 mL) is heatedunder nitrogen at 100° C. for 2 h, then partitioned between water andAcOEt. The organic phase is washed with water and brine, dried overMgSO₄, and concentrated under reduced pressure. FC (MeOH/CH₂Cl₂ 5:95)provides thiadiazole W-96 (261 mg). Recrystallization of 238 mg of thisfrom acetonitrile/toluene affords 205 mg of fine white crystals.

Physical characteristics are as follows:

mp: 156-157° C.

¹H-NMR δ2.92, 3.50, 7.2-7.3.

IR 3186, 1565, 1505 cm⁻¹

EI MS m/z221

Anal. Found: C, 54.51; H, 5.47; N, 25.26; S, 14.30.

Preparation 49 2-Amino-5-(butylamino)-1,3,4-thiadiazole (W-97) (Refer ToChart W.)

To a stirred, cooled (0° C. ) mixture of 2-amino-5-bromothiadiazole W-95(5.40 g) and of K₂HPO₄ (5.7 g) in DMF (20 mL) is added n-butylamine (5.9ml). The ice bath is removed and the mixture stirred at room temperaturefor 18 h, then partitioned between water and AcOEt. Continuousextraction with CH₂Cl₂ is necessary to remove all product from theaqueous phase. The combined organic phase is dried over MgSO₄ andconcentrated under reduced pressure. FC (MeOH/CH₂Cl₂ 7:93) providesthiadiazole W-97 (3.49 g). Recrystallization from acetonitrile/tolueneaffords 3.34 g of white needles.

Physical characteristics are as follows:

mp: 152-154° C.

¹H-NMR δ0.94, 1.4, 1.6, 3.21, 3.6.

IR 3184, 2957, 1562, 1507 cm⁻¹

El MS m/z 173

Preparation 502-Amino-5-([2-[(tert-butoxy)amido]ethyl}amino)-1,3,4-thiadiazole (W-98)(Refer to Chart W.)

A mixture of 2-amino-5-bromo-1,3,4-thiadiazole W-95 (5.40 g), of K₂HPO₄(7.84 g) and Boc-ethylenediamine (9.60 g) in DMF (20 mL) is stirred atr.t. for 18 h. The solid paste obtained is recrystallized fromacetonitrile/water to provide thiadiazole W-98 (6.18 g) as pinkplatelets.

Physical characteristics are as follows:

mp: 219-220° C.

¹H-NMR (CD₃OD) δ1.40, 3.2-3.3.

IR 2989, 1676, 1577, 1512, 1366 cm⁻¹

El MS m/z 260

Preparation 51 Amino-1,3-benzodioxol-5-ylacetonitrile (W-99) (Refer toChart W.)

Piperonal (6.00 g) is dissolved in THF (25 mL) and aq. NH₃ (58%, 4.2mL), NH₄Cl (3.3 g) and KCN (3.9 g) are added. The mixture is stirredefficiently for 24 h. MgSO₄ is added and the mixture stirred for 30min., filtered and washed with THF. The filtrate is evaporated underreduced pressure and the residue purified by FC (Et₂O/petrol ether1:2,→2:1,→Et₂O). Aminonitrile W-99 is obtained as a brown, unstable oil(2.87 g). The hydrochloride salt is precipitated from sat. HCl/Et₂O foranalytical purposes.

Physical characteristics are as follows:

Free amino nitrile:

R_(f)=0.45 (AcOEt/hexanes 1:1).

Hydrochloride salt:

mp: 159-164° C. (dec).

¹H-NMR (D₂O, 300 MHz) δ7.03, 7.02, 6.88, 5.96, 5.58.

¹³C-NMR (D₂O, 75 MHz) δ149.43, 148.22, 122.80, 121.74, 115.21, 109.16,108.00, 102.07.

MS (EI) m/z 176 (M⁺), 160, 150, 122.

Anal. Found: C, 50.59; H, 4.25; N, 12.90.

Preparation 52[(2-Amino-1,3,4-thiadiazol-5-yl)amino]-1,3-benzodioxol-5-ylacetonitrile(W-100) (Refer to Chart W.)

According to GP I starting from thiadiazole W-95 (2.70 g), aminonitrileW-99 (2.39 g) and DIPEA (2.70 mL) in DMF (60 mL), the product ispurified by FC (AcOEt/hexanes 3:1→AcOEt). Nitrile W-100 is isolated as abrown powder (1.70 g).

Physical characteristics are as follows:

R_(f)=0.10 (AcOEt/hexanes 1:1).

mp: 144° C. (dec).

¹H-NMR (CD₃OD, 300 MHz) δ7.06, 7.02, 6.87, 5.99, 5.74.

¹³C-NMR (CD₃OD, 75 MHz) δ162.92, 158.60, 148.61, 148.39, 127.48, 120.91,117.95, 108.07, 107.34, 101.66.

HRMS (EI) 275.0461.

Preparation 53 N-(2-Amino-1,3,4-thiadiazol-5-yl)phenylalanine methylester (W-101) (Refer to Chart W.)

According to GP I starting from thiadiazole W-95 (1.50 g), phenylalaninemethyl ester hydrochloride (1.80 g) and DIPEA (4.20 mL) in DMF (30 mL),the product is purified by FC (AcOEt/hexanes 3:1→AcOEt). Ester W-101 isobtained as a white powder (0.22 g).

Physical characteristics are as follows:

R_(f)=0.05 (AcOEt/hexanes 1:1).

mp: 186-189° C.

¹H-NMR (CD₃OD, 300 MHz) δ7.27-7.09, 4.57, 3.67, 3.17, 3.01.

¹³C-NMR (CD₃OD, 75 MHz) δ172.74, 161.75, 160.65, 136.77, 128.85, 128.02,126.45, 58.07, 51.16, 37.48.

MS (EI) m/z: 278 (M⁺), 219, 187, 155, 127, 116.

Anal. Found: C, 51.61; H, 4.98; N, 19.91.

Preparation 54 N-(2-Amino-1,3,4-thiadiazol-5-yl)-D-phenylalanine methylester (W-102) (Refer to Chart W.)

According to GP I starting from thiadiazole W-95 (1.50 g),D-phenylalanine methyl ester hydrochloride (1.80 g) and DIPEA (4.20 mL)in DMF (30 mL), the product is purified by FC (AcOEt/hexanes 3:1→AcOEt).Ester W-102 is obtained as a white powder (0.19 g).

Physical characteristics are as follows:

R_(f)=0.05 (AcOEt/hexanes 1:1).

mp: 186-189° C.

¹H-NMR (CD₃OD, 300 MHz) δ7.26-7.19, 4.57, 3.66, 3.17, 3.01.

¹³C-NMR (CD₃OD, 75 MHz) δ172.77, 161.75, 160.66, 136.76, 128.86, 128.03,126.46, 58.07, 51.19, 37.48.

MS (EI) m/z: 278 (M⁺), 219, 187, 155, 127, 116.

Anal. Found: C, 51.57; H, 5.14; 19.86.

Preparation 55 2-(1,3-Benzodioxol-5-yl)glycine (W-103) (Refer to ChartW.)

Prepared according to literature procedure (E H W Boehm, R E Bambury, RJ Baumann, R C Erickson, B L Harrison, P F Hoffman, F J McCarty, R ASchnettler, M J Vaal, D L Wenstrup, J. Med. Chem. 1980, 23, 405).

Physical characteristics are as follows:

¹H-NMR (d₆-DMSO, 300 MHz) δ6.22, 6.84, 5.97, 4.10.

MS (EI) m/z 195 (M⁺), 150, 123, 93.

HRMS (EI) 195.0530.

Preparation 56 2-(1,3-Benzodioxol-5-yl)glycine tert-butyl ester (W-104)(Refer to Chart W.)

2-(1,3-Benzodioxol-5-yl)glycine W-95 (5.00 g) is dissolved in a dioxane(50 mL) and conc. H₂SO₄ (3.90 mL) mixture. Liquid i-butylene (50 mL) isadded, the flask rapidly tightly closed and shaken for 24 h. The mixtureis poored into a mixture of 1M NaOH/H₂O, ice and AcOEt. After shaking,the phases are separated and the aq. phase is extracted with AcOEt (1×).The combined org. phases are dried over MgSO₄. Removing the solventunder reduced pressure yields an oil containing 77% (^(l)H-NMR) of esterW-104 (6.65 g, 5.10 g of product).

Physical characteristics are as follows:

¹H-NMR (CDCl₃, 300 MHz) δ6.85-6.80, 6.74, 5.94, 4.42, 1.37.

Preparation 57N-(2-Amino-1,3,4-thiadiazo-5-yl)-2-(1,3-benzodioxol-5-yl)glycinetert-butyl ester (W-105) (Refer to Chart W.)

According to GP I starting from thiadiazole W-95 (3.65 g), tert-butylester W-104 (5.10 g), DIPEA (6.8 mL) and DMF (150 mL). Crystallizationof the crude from AcOEt/hexanes yieldsester W-105 as a white powder(6.15 g).

Physical characteristics are as follows:

R_(f)=0.05 (AcOEt/hexanes 1:1).

¹H-NMR (d₆-DMSO, 300 MHz) δ7.42, 6.92-6.86, 6.26, 5.99, 5.05, 1.30.

¹³C-NMR (d₆-DMSO, 75 MHz) δ170.70, 160.60, 158.81, 147.73, 147.43,131.33, 121.48, 108.67, 108.10, 101.61, 81.33, 61.03, 28.00.

MS (EI) m/z 350 (M⁺), 249, 179, 148, 57.

HRMS (EI) 350.1043.

Preparation 58 2-(1,3-Benzodioxol-4-yl)glycine (W-106) (Refer to ChartW.)

Prepared according to literature procedure (E H W Boehm, R E Bambury, RJ Baumann, R C Erickson, B L Harrison, P F Hoffman, F J McCarty, R ASchnettler, M J Vaal, D L Wenstrup, J. Med. Chem. 1980, 23, 405).

Physical characteristics are as follows:

¹H-NMR (d₆-DMSO, 300 MHz) δ6.62, 6.00, 5.97, 4.23.

MS (EI) m/z 195 (M⁺), 150, 123, 93, 75.

HRMS (EI) 195.0527.

Preparation 59 2-(1,3-Benzodioxol-4-yl)glycine tert-butyl ester (W-107)(Refer to Chart W.)

2-(1,3-Benzodioxol-4-yl)glycine W-106 (1.72 g) is dissolved in a dioxane(20 mL) and conc. H₂SO₄ (1.35 mL) mixture. Liquid i-butylene (20 mL) isadded, the flask rapidly tightly closed and shaken for 24 h. The mixtureis poored in a mixture of 1M NaOH/H2O, ice and AcOEt. After shaking, thephases are separated and the aq. phase is extracted with AcOEt (1×). Thecombined org. phases are dried over MgSO₄. Removing the solvent underreduced pressure yields an oil containing 78% (¹H-NMR) of ester W-107(1.46 g, 1.14 g of product).

Physical characteristics are as follows:

¹H-NMR (CDCl₃, 300 MHz) δ6.79-6.72, 5.97, 5.94, 4.57, 1.39.

Preparation 60N-(2-Amino-1,3,4-thiadiazo-5-yl)-2-(1,3-benzodioxol-4-yl)glycinetert-butyl ester (W-108) (Refer to Chart W.)

According to GP I starting from thiadiazole W-95 (0.83 g),2-(1,3-benzodioxol-4-yl)glycine tert-butyl ester W-107 (1.14 g), DIPEA(1.5 mL) and DMF (30 mL). Crystallization of the crude fromAcOEt/hexanes yields ester W-108 as a white powder (0.87 g).

Physical characteristics are as follows:

R_(f)=0.05 (AcOEt/hexanes 1:1).

¹H-NMR (d₆-DMSO, 300 MHz) δ7.52, 6.90-6.78, 6.42, 6.03, 6.02, 5.30,1.32.

¹³C-NMR (d-DMSO, 75 MHz) δ169.83, 160.87, 158.70, 147.55, 145.68,122.18, 120.39, 119.02, 108.77, 101.50, 81.61, 55.41, 27.99.

MS (EI) m/z 250 (M⁺), 249, 233, 148, 57.

Anal. Found: C, 51.05; H, 5.35; N, 15.91.

Preparation 61

2-Amino-5-[N-(1,3-benzodioxol-5-ylmethyl)amino]-1,3,4-thiadiazole(X-109) (Refer to Chart X.)

According to GP I starting from thiadiazole W-95 (1.00 g),piperonylamine (0.83 mL), DIPEA (1.85 mL) and DMF (10 mL). Purificationof the crude by FC (AcOEt→MeOH/AcOEt 1:19→MeOH/CH₂Cl₂ 1:9) yieldsthiadiazole X-109 as a white powder (99 mg).

Physical characteristics are as follows:

R_(f)=0.02 (AcOEt/hexanes 1:1).

mp: 164-187° C.

¹H-NMR (d₆-DMSO, 300 MHz) δ7.18, 6.87, 6.83, 7.78, 6.24, 5.96, 4.20.

¹³C-NMR (d₆-DMSO, 75 MHz) δ160.32, 159.77, 147.62, 146.55, 133.78,121.20, 108.56, 108.42, 101.25, 47.73.

MS (EI) m/z 250 (M⁺), 208, 135, 105, 77,51.

HRMS (EI) 250.0528.

Preparation 62

N-(2-Amino-1,3,4-thiadiazol-5-yl)tyrosine tert-butyl ester (X-110)(Refer to Chart X.)

According to GP I starting from thiadiazole W-95 (760 mg), tyrosinetert-butyl ester hydrochloride (1.16 g), DIPEA (1.80 mL) and DMF (20mL). Crystallization of the crude from AcOEt/hexanes yields ester X-110as a white powder (0.98 g).

Physical characteristics are as follows:

R_(f)=0.25 (AcOEt).

mp: 121-123° C.

¹H-NMR (CD₃OD, 300 MHz) δ8.20, 7.27, 6.93, 4.60, 3.08, 1.60.

¹³C-NMR (CD₃OD, 75 MHz) δ171.71, 161.65, 160.84, 155.95, 130.07, 127.47,114.68, 81.37, 59.02, 36.85, 26.81.

MS (EI) m/z 336 (M⁺), 263, 235, 173, 156, 116, 107, 57.

HRMS (EI) 336.1259.

Preparation 63N¹-(2-Amino-1,3,4-thidiazol-5-yl)-N⁵-[(benzoxy)carbonyl]lysinetert-butyl ester (X-111) (Refer to Chart X.)

According to GP I starting from thiadiazole W-95 (730 mg),N⁵-[(benzoxy)-carbonyl]lysine tert-butyl ester hydrochloride (1.50 g),DIPEA (2.05 mL) and DMF (25 mL). Crystallization of the crude fromAcOEt/hexanes yields ester X-111 as a white powder (0.96 g).

Physical characteristics are as follows:

R_(f)=0.25 (AcOEt).

mp: 131-132° C.

¹H-NMR (CD₃OD, 300 MHz) δ7.33, 5.05, 4.13, 3.10, 1.95-1.45, 1.44.¹³C-NMR (CD₃OD, 75 MHz) δ172.40, 161.58, 161.15, 157.53, 137.04, 128.06,127.54, 127.36, 81.29, 65.92, 57.39, 40.09, 29.11, 26.89, 22.63, 19.24.

Anal. Found: C, 55.08; H, 6.69; N, 16.22.

Preparation 64 N-(2-Amino-1,3,4-thiadiazol-5-yl)leucine tert-butyl ester(X-112) (Refer to Chart X.)

According to GP I starting from thiadiazole W-95 (1.00 g), leucinetert-butyl ester hydrochloride (1.50 g), DIPEA (2.80 mL) and DMF (10mL). Purification of the crude by FC (AcOEt/hexanes 1:1 AcOEt) yieldsester X-112 as a white powder (1.06 g).

Physical characteristics are as follows:

R_(f)=0.20 (AcOEt).

mp: 138-141° C.

¹H-NMR (CD₃OD, 300 MHz) δ4.38, 2.01, 1.82, 1.65, 1.18.

¹³C-NMR (CD3OD, 75 MHz); two rotamers visible δ176.62, 172.89, 172.71,163.47, 162.05, 160.64, 81.20, 72.76, 56.05, 42.83, 40.87, 35.58, 30.27,26.86, 24.77, 21.87, 20.65.

MS (EI) m/z 286 (M⁺), 269, 230, 213, 185, 156, 143, 129, 116, 57.

HRMS (EI) 286.1461.

Preparation 65 N-(2-Amino-1,3,4-thiadiazol-5-yl)proline tert-butyl ester(X-113) (Refer to Chart X.)

According to GP I starting from thiadiazole W-95 (1.00 g), prolinetert-butyl ester hydrochloride (1.46 g), DIPEA (2.80 mL) and DMF (10mL). Purification of the crude by FC (AcOEt/hexanes 1:1→AcOEt) yieldsester X-113 as a white powder (0.55 g).

Physical characteristics are as follows:

R_(f)=0.25 (AcOEt).

mp: 141-146° C.

¹H-NMR (CD₃OD, 300 MHz) δ4.20, 3.58-3.41, 2.37-2.31, 2.09-2.01, 1.45.

¹³C-NMR (CD₃OD, 75 MHz) δ171.91, 161.09, 160.95, 81.64, 63.13, 50.45,30.29, 26.79, 23.45.

MS (EI) m/z 270 (M⁺), 214, 197, 169, 142, 128, 100, 70, 57.

HRMS (EI) 270.1154.

Preparation 66 N-(2-Amino-1,3,4-thiadiazol-5-yl)methionine tert-butylester (X-15 114) (Refer to Chart X.)

According to GP I starting from thiadiazole W-95 (750 mg), methioninetert-butyl ester hydrochloride (1.00 g), DIPEA (2.10 mL) and DMF (20mL). Crystallization of the crude from AcOEt/hexanes yields ester X-1 14as a white powder (0.60 g).

Physical characteristics are as follows:

R_(f)=0.25 (AcOEt).

mp: 172-173° C.

¹H-NMR (CD₃OD, 300 MHz) δ4.31, 2.62-2.56, 2.16-1.92, 2.08, 1.45.

¹³C-NMR (CD₃OD, 75 MHz) δ172.04, 161.71, 161.09, 81.47, 56.52, 31.38,29.75, 26.87, 13.85.

MS (EI) m/z 304 (M⁺), 257, 258, 248, 231, 203, 185, 155, 141, 128, 100,57.

Anal. Found: C, 43.59; H, 6.59; N, 18.55.

Preparation 67 N-(2-Amino-1,3,4-thiadiazol-5-yl)tryptophane tert-butylester (X-115) (Refer to Chart X.)

According to GP I starting from thiadiazole W-95 (610 mg), tryptophanetert-butyl ester hydrochloride (1.00 g), DIPEA (1.70 mL) and DMF (mL).The crude ester X-115 is dried under high vacuum (0.86 g).

Physical characteristics are as follows:

R_(f)=0.25 (AcOEt).

¹H-NMR (CD₃OD, 300 MHz) δ7.55, 7.31, 7.09-6.99, 4.54, 3.31-3.21, 1.29.

¹³C-NMR (CD₃OD, 75 MHz) δ173.95, 172.07, 163.45, 161.62, 160.98, 136.56,127.54, 123.11, 120.95, 118.31, 110.78, 81.22, 58.40, 35.54, 30.23,26.78.

MS (EI) m/z 359 (M⁺), 243, 187, 130, 57.

HRMS (EI) 359.1399.

Preparation 68 N-(2-Amino-1,3,4-thiadiazol-5-yl)-O⁷-tert-butyltyrosinetert-butyl ester (X-116) (Refer to Chart X.)

According to GP I starting from thiadiazole W-95 (580 mg),O⁷-tert-butyltyrosine tert-butyl ester hydrochloride (1.00 g), DIPEA(1.65 mL) and DMF (20 mL). Crystallization of the crude fromAcOEt/hexanes yields ester X-116 as a white powder (0.89 g).

Physical characteristics are as follows:

R_(f)=0.35 (AcOEt).

mp: 149-151° C.

¹H-NMR (CD₃OD, 300 MHz) δ7.15, 6.90, 4.42, 3.03, 2.89, 1.35, 1.30.

¹³C-NMR (CDCl₃, 75 MHz) δ171.58, 161.69, 160.74, 153.91, 132.01, 129.66,123.79, 81.45, 78.13, 58.82, 37.10, 27.80, 26.85.

MS (EI) m/z 392 (M⁺), 276, 235, 220, 173, 164, 116, 107, 57.

HRMS (EI) 392.1885.

Anal. Found: C, 57.96; H, 7.25; N, 13.80.

Preparation 69 N-(2-Amino-1,3,4-thiadiazol-5-yl)aspartic aciddi-tert-butyl ester (X-117) (Refer to Chart X.)

According to GP I starting from thiadiazole W-95 (640 mg), aspartic aciddi-tert-butyl ester hydrochloride (1.00 g), DIPEA (1.80 mL) and DMF (20mL). Crystallization of the crude from AcOEt/hexanes yields ester X-117as a white powder (0.84 g).

Physical characteristics are as follows:

R_(f)=0.30 (AcOEt).

mp: 142-146° C.

¹H-NMR (CD₃OD, 300 MHz) δ4.50, 2.81, 2.71, 1.45, 1.44.

¹³C-NMR (CD₃OD, 75 MHz) δ170.46, 169.90, 161.85, 160.75, 81.75, 81.00,54.20, 37.39, 26.94, 26.83.

MS (EI) m/z 344 (M⁺), 288, 232, 215, 187, 143, 57.

HRMS (EI) 344.1512.

EXAMPLE 2438-Hydroxy-N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-7-quinolinecarboxamide(Y-118) (Refer to Chart Y)

According to GP II, starting from anhydride U-1 (50 mg), pyridiniumchloride 10.8 mg), 2-amino-5-(trifluoromethyl)-1,3,4-thiadiazole (15.7mg) and CHCl₃ (2 mL), amide Y-118 precipitates as a yellow powderwithout adding any aq. 1M HCl sol. 16.5 mg).

Physical characteristics are as follows:

mp: 300-302° C. (dec).

¹H-NMR (d₆-DMSO, 300 MHz) δ8.88, 8.08, 7.96, 7.14.

¹³C-NMR (d₆-DMSO, 75 MHz) δ165.70, 163.15, 162.17, 144.83, 142.72,135.49, 133.44, 130.08, 124.58, 112.61, 109.85.

MS (EI) m/z 340 (M⁺), 172, 116, 89, 63.

HRMS (EI) 340.0234.

Anal. Found: C, 45.45; H, 2.25; N, 16.33.

EXAMPLE 244N-(5-Bromo-1,3,4-thiadiazol-2-yl)-8-hydroxy-7-quinolinecarboxamide(Y-119) (Refer to Chart Y)

According to GP II, starting from anhydride U-1 (100 mg), pyridiniumchloride (21.4 mg), 2-amino-5-bromo-1,3,4-thiadiazole W-95 (43 mg) andCH₂ClCH₂HCl (2 mL), amide Y-119 precipitate as an orange powder withoutadding any aq. 1M HCl sol. (56 mg).

Physical characteristics are as follows:

mp: 250° C. (dec).

¹H-NMR (d-TFA, 300 MHz) δ9.35, 9.30, 8.67, 8.37, 8.03.

MS (EI) m/z 350 and 352 (M⁺), 271, 172, 116, 89, 63.

HRMS (EI) 349.9469.

Anal. Found: C, 41.88; H, 2.31; N, 14.46.

EXAMPLE 2458-Hydroxy-N-[5-(2-phenylethyl)amino-1,3,4-thiadiazol-2-yl]-7-quinolinecarboxamidemonohydrochloride (Y-120) (Refer to Chart Y)

According to GP II, starting from anhydride U-1 (50 mg), pyridiniumchloride (10.8 mg), 2-amino-5-(2-phenylethyl)amino-1,3,4-thiadiazoleW-96 (20.5 mg) and CHCl₃ (2 mL), amide Y-120 is obtained as a yellowpowder (20 mg).

Physical characteristics are as follows:

¹H-NMR (d₆-DMSO, 300 MHz) δ8.93, 8.84, 8.07, 7.90, 7.35-7.10, 3.58,2.91.

¹³C-NMR (d₆-DMSO, 75 MHz) δ166.62, 163.52, 160.78, 144.45, 143.73,138.88, 134.85, 132.99, 129.60, 129.31, 128.88, 126.92, 124.48, 113.69,111.70, 46.39, 34.45.

MS (EI) m/z 357 (M⁺), 186, 172, 116, 89.

HRMS (EI) 392.1181.

EXAMPLE 246N-[5-(Butylamino)-1,3,4-thiadiazol-2-yl]-8-hydroxy-7-quinolinecarboxamidemonohydrochloride (Y-121) (Refer to Chart Y)

According to GP II, starting from anhydride U-1 (50 mg), pyridiniumchloride (10.8 mg), 2-amino-5-(butylamino)-1,3,4-thiadiazole W-97 (16.0mg) and CHCl₃ (2 mL), amide Y-121 is obtained as a yellow powder (22mg).

Physical characteristics are as follows:

¹H-NMR (d₆-DMSO, 300 MHz) δ8.90, 8.07, 7.97, 7.25, 3.35, 1.58, 1.36,0.90.

¹³C-NMR (d₆-DMSO, 75 MHz) δ166.52, 163.64, 160.67, 145.13, 143.23,134.55, 133.17, 129.81, 127.79, 124.57, 113.40, 111.07, 45.12, 30.37,19.87, 14.00.

HRMS (EI) 343.1084.

EXAMPLE 247N-[5-({2-[(tert-Butoxy)amido]ethyl}amino)-1,3,4-thiadiazol-2-yl]-8-hydroxy-7-quinolinecarboxamidemonohydrochloride (Y-122) (Refer to Chart Y)

According to GP II, starting from anhydride U-1 (50 mg), pyridiniumchloride (10.8 mg),2-amino-5-({2-[(tert-butoxy)amido]ethyl}amino)-1,3,4-thiadiazole W-98(24 mg) and CHCl₃ (2 mL), 1M HCl/H₂O is not added, but the sol. dilutedin some CHCl₃, washed with an aq. buffer sol. at pH 4 (1×), dried overMgSO₄, filtered and the solvent removed under reduced pressure.Purification of the residue by FC (AcOEt→MeOH/CH₂Cl₂ 1:9) leads to amideY-122 as a yellow powder (15 mg).

Physical characteristics are as follows:

¹H-NMR (CD₃OD, 300 MHz) δ8.95, 8.83, 8.25, 7.95, 7.43, 3.49, 3.31, 1.43.

¹³C-NMR (d₆-DMSO, 75 MHz) δ168.49, 166, 163.84, 156.12, 146.36, 138.73,135.28, 132.47, 130.75, 128.27, 123.60, 113.14, 111.63, 78.15, 44.09,36.25, 28.70.

MS (FAB) m/z 431 (MH⁺), 260, 204, 172, 57.

HRMS (FAB) 431.1494.

EXAMPLE 248N-{5-[(1,3-Benzodioxol-5-cyanomethyl)amino]-1,3,4-thiadiazol-2-yl}-8-hydroxy-7-quinolinecarboxamidemonohydrochloride (Y-123) (Refer to Chart Y)

According to GP II, starting from anhydride U-1 (100 mg), pyridiniumchloride (21.4 mg),2-amino-1,3,4-thiadiazol-5-yl)amino]-1,3-benzodioxol-5-ylacetonitrileW-100 (51.0 mg), CHCl₃ (4 mL) and THF (0.4 mL), amide Y-123 is obtainedas a yellow powder (35 mg).

Physical characteristics are as follows:

¹H-NMR (d₆-DMSO, 300 MHz) δ9.00, 8.89, 8.77, 8.14, 7.98, 7.43, 7.14,7.11, 7.00, 6.07, 6.02.

¹³C-NMR (d₆-DMSO, 75 MHz) δ179.5, 160.81, 148.47, 148.22, 145.03,144.09, 142.28, 134.05, 132.50, 129.37, 127.79, 124.43, 121.88, 118.98,115.41, 114.28, 109.01, 108.42, 102.07, 60.87, 48.17.

MS (FAB) m/z 447 (MH⁺), 276, 172.

HRMS (FAB) 447.0866.

EXAMPLE 249(S)—N-[5-({Benzyl[(methoxy)carbonyl]methyl}amino)-1,3,4-thiadiazol-2-yl]-8-hydroxy-7-quinolinecarboxamidemonohydrochloride (Y-124) (Refer to Chart Y)

According to GP II, starting from anhydride U-1 (200 mg), pyridiniumchloride (42 mg), N(2-amino-1,3,4-thiadiazo-5-yl)phenylalanine methylester W-101 (103 mg), and CHCl₃ (8 mL), amide Y-124 is obtained as ayellow powder (100 mg).

Physical characteristics are as follows:

¹H-NMR (d₆-DMSO, 300 MHz) δ8.98, 8.86, 7.50, 8.12, 7.94, 7.40, 7.27,4.59, 3.14, 3.06.

¹³C-NMR (d₆-DMSO, 75 MHz) δ172.18, 167.06, 162.24, 145.07, 143.62,137.14, 134.41, 132.52, 129.65, 129.27, 128.81, 127.23, 124.36, 115.11,113.94, 58.44, 52.56, 37.4.

MS (EI) m/z 449 (M⁺), 390, 372, 358, 287, 187, 172, 116.

HRMS (FAB) 450.1233.

EXAMPLE 250(R)—N-[5-({Benzyl[(methoxy)carbonyl]methyl}amino)-1,3,4-thiadiazol-2-yl]-8-hydroxy-7-quinolinecarboxamidemonohydrochloride (Y-125) (Refer to Chart Y)

According to GP II, starting from anhydride U-1 (200 mg), pyridiniumchloride (42 mg), N-(2-amino-1,3,4thiadiazo-5-yl)-D-phenylalanine methylester W-102 (103 mg), and CHCl3 (8 mL), amide Y-125 is obtained as ayellow powder (105 mg).

Physical characteristics are as follows:

¹H-NMR (d₆-DMSO, 300 MHz) δ8.98, 8.86, 7.50, 8.12, 7.94, 7.40, 7.27,4.59, 3.14, 3.06.

¹³C-NMR (d₆-DMSO, 75 MHz) δ172.18, 167.06, 162.24, 145.07, 143.62,137.14, 134.41, 132.52, 129.65, 129.27, 128.81, 127.23, 124.36, 115.11,113.94, 58.44, 52.56, 37.41.

MS (EI) m/z 449 (M⁺), 390, 372, 358, 287, 187, 172, 116.

HRMS (FAB) 450.1233.

EXAMPLE 251N-[5-({1,3-Benzodioxol-5-yl-[(tert-butoxy)carbonyl]methyl}-amino)-1,3,4-thiadiazol-2-yl]-8-hydroxy-7-quinolinecarboxamidesemihydrate (Y-126) (Refer to Chart Y)

According to GP IV, starting from ester U-3 (131 mg),N-(2-amino-1,3,4-thiadiazo-5-yl)-2-(1,3-benzodioxol-5-yl)glycinetert-butyl ester W-105 (197 mg,), DIPEA (0.10 mL) and CH₂Cl₂ (6 mL).Stirred for 4 h, then overnight with MeOH. After adding MeOH, amideY-126 precipitated as a yellow powder that is filtered and dried (120mg).

Physical characteristics are as follows:

mp: 227-229° C.

¹H-NMR (d₆-DMSO, 300 MHz) δ8.92, 8.63, 8.05, 7.77, 7.25, 6.97, 6.92,6.02, 5.21, 1.33.

¹³C-NMR (d₆-DMSO, 75 MHz), δ169.80, 147.26, 147.04, 131.92, 130.28,123.54, 121.02, 108.24, 107.65, 101.12, 81.04, 60.47, 27.43.

MS (EI) m/z 521 (M⁺), 465, 447, 420, 249, 172, 56.

HRMS (FAB) δ22.1452.

Anal. Found: 56.66; H, 4.49; N, 13.30.

EXAMPLE 252N-[5-({1,3-Benzodioxol-4-yl-[(tert-butyloxy)carbonyl]methyl}amino)-1,3,4-thiadiazol-2-yl]-8-hydroxy-7-quinolinecarboxamidesemihydrate (Y-127) (Refer to Chart Y)

According to GP IV, starting from ester U-3 (133 mg),N-(2-amino-1,3,4-thiadiazo-5-yl)-2-(1,3-benzodioxol-4-yl)glycinetert-butyl ester W-108 (200 mg,), DIPEA (0.10 mL) and CH₂Cl₂ (6 mL),stirred for 4 h, then overnight with MeOH. The solution is diluted withsome CH₂Cl₂, washed with sat. NaHCO₃/H₂O (1×) and an aq. buffer sol. atpH 4 (1×), an emulsion formed that separated slowly into two phases. Theorg. phase is dried over MgSO₄, filtered and the solvent removed underreduced pressure. The residue is triturated with AcOEt, filtered anddried. Amide Y-127 is obtained as a yellow powder (140 mg).

Physical characteristics are as follows:

¹H-NMR (d₆-DMSO, 300 MHz) δ8.88, 8.65, 8.20, 8.05, 7.83, 7.26,7.00-6.80, 6.05, 5.42, 1.33.

¹³C-NMR (d₆-DMSO, 75 MHz) δ168.86, 159.12, 147.08, 145.22, 131.94,128.37, 123.59, 121.77, 119.90, 117.96, 113.57, 108.53, 101.04, 81.36,54.93, 27.41.

MS (FAB) m/z 522 (MH⁺), 598, 466, 420, 249, 57.

HRMS (FAB) 522.1447.

EXAMPLE 253N-{5-[(1,3,-Benzodioxol-5-ylmethyl)amino]-1,3,4-thiadiazol-2-yl}-8-hydroxy-7-quinolinecarboxamide(Y-128) (Refer to Chart Y)

According to GP IV, starting from ester U-3 (85 mg),2-amino-5-[N-(1,3-benzodioxol-5-ylmethyl)amino]-1,3,4-thiadiazole X-109(90 mg), DIPEA (70 μL) and CH₂Cl₂ (4 mL). Stirred for 20 h, then for 5 hwith MeOH. After adding MeOH, a yellow precipitate appears, that isfiltered and dried (40 mg); this precipitate proved to be the not quitepure amide Y-128 and was not further purified due to its low solubility.

Physical characteristics are as follows:

mp: 280-282° C.

¹H-NMR (d₆-DMSO, 300 MHz) δ8.86, 8.53, 8.02, 7.85, 7.76, 7.22, 6.93,6.85, 5.97, 4.34.

¹³C-NMR (d₆-DMSO, 75 MHz), due to the low solubility of the product, anincomplete set of signals is obtained δ147.72, 146.73, 133.15, 132.42,123.95, 121.36, 121.23, 108.66, 108.54, 101.33.

MS (EI) m/z 421 (M⁺), 270, 250, 208, 172, 150, 135, 116.

HRMS (EI) 421.0827.

EXAMPLE 254(S)—N-[5-({[(tert-Butoxy)carbonyl]-[4-hydroxybenzyl]methyl)-amino)-1,3,4-thiadiazol-2-yl]-8-hydroxy-7-quinolinecarboxamide(Y-129) (Refer to Chart Y)

According to GP IV, starting from ester U-3 (500 mg),N-(2-amino-1,3,4-thiadiazol-5-yl)tyrosine tert-butyl ester X-110 (720mg), DIPEA (0.36 mL) and CH₂Cl₂ (10 mL). Stirred for 7 h, then overnightwith MeOH. The solvent is almost completely removed until a consistentprecipitate appeared that is filtered, washed with AcOEt and MeOH anddried under high vacuum. The product obtained as a yellow powder (0.53g) was a not unpurified mixture of amide Y-129 (80 mol % by ¹H-NMR) andacetylated product (20 mol %).

Physical characteristics are as follows:

¹H-NMR (d₆-DMSO, 300 MHz) δ8.85, 8.54, 8.01, 7.90-7.70, 7.30-6.95,4.60-4.30, 3.15-2.85, 1.31.

MS (ES) m/z Neg. mode: 506 (MH⁺), 548 (acetylated product+H⁺).

EXAMPLE 255(S)—N-[5-({5-[Benzoxy]amido-1-[(tert-butoxy)carbonyl]pentyl}-amino)-1,3,4-thiadiazol-2-yl·3-8-hydroxy-7-quinolinecarboxamide(Y-130) (Refer to Chart Y)

According to GP IV, starting from ester U-3 (500 mg)),N1-(2-amino-1,3,4-thiadiazol-5-yl)-N⁵-[(benzoxy)carbonyl]lysinetert-butyl ester X-111 (0.93 g), DIPEA (0.36 mL) and CH₂Cl₂ (10 mL).Stirred for 7 h, then overnight with MeOH. The solvent is almostcompletely removed until a consistent precipitate appears. It isfiltered, washed with AcOEt and MeOH and dried. A yellow foam isobtained (0.50 g) that proved to contain about 90 mol % (¹H-NMR) ofamide Y-130.

Physical characteristics are as follows:

¹H-NMR (d₆-DMSO, 300 MHz) δ8.76, 8.35, 7.95, 7.65-7.50, 7.35-7.20, 7.02,4.98, 4.15-4.05, 2.97, 1.69, 1.38, 1.23.

¹³C-NMR (d₆-DMSO, 75 MHz) δ171.76, 162.63, 155.98, 145.51, 138.21,137.14, 131.94, 128.22, 127.77, 127.61, 122.97, 122.41, 80.37, 64.99,56.82, 53.39, 31.16, 28.96, 27.56, 22.57.

MS (FAB) m/z 607 (MH⁺), 551, 288, 172.

HRMS (FAB) 607.2345.

EXAMPLE 256(S)—N-[5-({1-[(tert-Butoxy)carbonyl]-3-methylbutyl}amino)-1,3,4-thiadiazol-2-yl]-8-hydroxy-7-quinolinecarboxamidemonohydrate (Y-131) (Refer to Chart Y)

According to GP IV, starting from ester U-3 (0.97 g)),N-(2-amino-1,3,4-thiadiazol-5-yl)leucine tert-butyl ester X-112 (1.18g), DIPEA (0.70 mL) and CH₂Cl₂ (20 mL). Stirred for 7 h, then overnightwith MeOH. Amide Y-131 appears as an orange precipitate that isfiltered, washed with AcOEt and dried under high vacuum (440 mg).

Physical characteristics are as follows:

mp: 214-5° C.

¹H-NMR (d₆-DMSO, 300 MHz) δ8.87, 8.61, 8.05, 7.83-7.65, 7.24, 4.14,1.85-1.70, 1.65-1.50, 1.38, 0.92, 0.87.

¹³C-NMR (d₆-DMSO, 75 MHz) δ172.62, 165.76, 163.20, 159.98, 152.80,145.62, 140.75, 137.60, 132.45, 128.73, 124.05, 113.91, 113.02, 80.99,55.96, 40.96, 28.10, 24.95, 23.09, 19.01.

MS (EI) m/z 457 (M⁺), 356, 345, 213, 172, 116, 89, 57.

HRMS (EI) 457.1781.

Kar-Fischer titration: 3.43% water (0.90 eq).

Anal. Found: C, 55.53; H, 6.02; N, 14.59.

EXAMPLE 257(S)—N-(5-{2-[(tert-Butoxy)carbonyl]pyrrolidin-N-yl}-1,3,4-thiadiazol-2-yl)-8-hydroxy-7-quinolinecarboxamidesemihydrate (Y-132) (Refer to Chart Y)

According to GP IV, starting from ester U-3 (710 mg),N-(2-amino-1,3,4-thiadiazol-5-yl)proline tert-butyl ester X-113 (816mg), DIPEA (0.51 mL) and CH₂Cl₂ (14 mL). Stirred for 7 h, then overnightwith MeOH. Amide Y-132 is obtained as an orange precipitate that isfiltered, washed with AcOEt and dried under high vacuum (955 mg).

Physical characteristics are as follows:

mp: Turned white between 220° C. and 250° C., then decomposed between285° C. and 290° C.

¹H-NMR (d₆-DMSO, 300 MHz) δ8.87, 8.65, 8.05, 7.82, 7.22, 4.28,3.55-3.45, 2.40-2.20, 2.10-1.95, 1.39.

¹³C-NMR (d₆-DMSO, 75 MHz) δ171.57, 163, 160.42, 145.05, 141.5, 137,132.56, 128.94, 124.10, 113.67, 112.29, 81.40, 62.74, 50.80, 30.66,28.09, 24.04.

MS (EI) m/z 441 (M⁺), 340, 172, 116, 57.

HRMS (EI) 441.1472.

Karl-Fischer titration: 2.09% water (0.55 eq).

Anal. Found: C, 56.03; H, 5.32; N, 15.56.

EXAMPLE 258(S)—N-[5-({1-[(tert-Butoxy)carbonyl]-3-[methylmercapto]propyl}-amino)-1,3,4-thiadiazol-2-yl]-8-hydroxy-7-quinolinecarboxamidemonohydrate (Y-133) (Refer to Chart Y)

According to GP IV, starting from ester U-3 (450 mg),N-(2-amino-1,3,4-thiadiazol-5-yl)methionine tert-butyl ester X-114 (0.60g), DIPEA (0.33 mL) and CH₂Cl₂ (10 mL). Stirred for 7 h, then overnightwith MeOH. The orange-red amide Y-133 is filtered, washed with AcOEt anddried under high vacuum (0.60 g).

Physical characteristics are as follows:

mp: 204-205° C.

¹H-NMR (d₆-DMSO, 300 MHz) δ8.87, 8.61, 7.79, 7.23, 4.29, 2.57, 2.05,2.05-1.90, 1.39.

¹³C-NMR (d₆-DMSO, 75 MHz) δ171.50, 162.89, 162.86, 159.75, 145.20,140.35, 137.18, 137.14, 132.17, 128.47, 123.76, 113.55, 112.54, 80.98,56.08, 31.19, 29.69, 27.70, 14.67.

MS (EI) m/z 475 (M⁺), 401, 327, 270, 213, 172, 116, 61.

HRMS (FAB) 476.1427.

Karl-Fischer titration: 3.40% water (0.92 eq.).

Anal. Found: C, 51.12; H, 5.46; N, 13.99.

EXAMPLE 259(S)—N-[5-({1-[(tert-Butoxy)carbonyl]-2-indol-3-ylethyl}amino)-1,3,4-thiadiazol-2-yl]-8-hydroxy-7-quinolinecarboxamidemonohydrate (Y-134) (Refer to Chart Y)

According to GP IV, starting from ester U-3 (500 mg),N-(2-amino-1,3,4-thiadiazol-5-yl)tryptophane tert-butyl ester X-115 (770mg), DIPEA (0.36 mL) and CH₂Cl₂ (10 mL). Stirred for 7 h, then overnightwith MeOH. Amide Y-134 is obtained as a yellow precipitate that isfiltered, washed with AcOEt and dried under high vacuum (0.52 g).

Physical characteristics are as follows:

¹H-NMR (d₆-DMSO, 300 MHz) δ10.90, 8.87, 8.58, 8.04, 7.84, 7.77, 7.53,7.33, 7.23, 7.17, 7.06, 6.98, 4.48, 3.20-3.10, 1.27.

¹³C-NMR (d₆-DMSO, 75 MHz) δ171.77, 165.79, 162.99, 160.04, 152.93,145.67, 140.62, 137.69, 136.57, 132.44, 128.70, 127.68, 124.34, 124.02,121.44, 118.85, 118.77, 113.93, 113.04, 111.87, 109.91, 80.01, 58.39,48.86, 27.98.

MS (FAB) m/z 531 (MH⁺), 475, 288, 172.

HRMS (FAB) 531.1841.

Karl-Fischer titration: 2.61% water (0.79 eq.).

Anal. Found: C, 59.24; H, 5.13; N, 15.13.

EXAMPLE 260(S)—N-(5-{1-[(tert-Butoxy)carbonyl]-2-[4-(tert-butoxy)phenyl]-ethyl}amino)-1,3,4-thiadiazol-2-yl]-8-hydroxy-7-quinolinecarboxamidemonohydrate (Y-135) (Refer to Chart Y)

According to GP IV, starting from ester U-3 (500 mg),N-(2-amino-1,3,4-thiadiazol-5-yl)-O⁷-tert-butyltyrosine tert-butyl esterX-1 16 (840 mg), DIPEA (0.36 mL) and CH₂Cl₂ (10 mL). Stirred for 7 h,then overnight with MeOH. The solvent is partially removed under reducedpressure until amide Y-135 appears as a consistent orange precipitatethat is filtered and dried under high vacuum (0.80 g).

Physical characteristics are as follows:

mp: 124-125° C. (dec).

¹H-NMR (d₆-DMSO, 300 MHz) δ8.84, 8.56, 8.02, 7.77, 7.75, 7.17, 6.87,4.39, 2.97, 1.27, 1.23.

¹³C-NMR (d₆-DMSO, 75 MHz) δ170.95, 165.2, 162.29, 160.26, 153.53,145.16, 139.66, 137.74, 131.91, 131.57, 129.74, 128.08, 123.45, 123.37,113.19, 112.07, 80.57, 77.59, 58.36, 36.77, 28.39, 27.43.

MS (FAB) m/z 564 (MH⁺), 508, 337, 281, 172, 57.

HRMS (FAB) 564.2280.

Karl-Fischer titration: 2.25% water (0.72 eq.)

Anal. Found: C, 59.75; H, 6.01; N, 12.07.

EXAMPLE 261(S)—N-[5-({1,2-Di-[(tert-butoxy)carbonyl]ethyl}amino)-1,3,4-thiadiazol-2-yl]-8-hydroxy-7-quinolinecarboxamidemonohydrate (Y-136) (Refer to Chart Y)

According to GP IV, starting from ester U-3 (500 mg),N-(2-amino-1,3,4-thiadiazol-5-yl)aspartic acid di-tert-butyl ester X-117(740 mg), DIPEA (0.36 mL) and CH₂Cl₂ (10 mL). Stirred for 7 h, thenovernight with MeOH. The solvent is removed under reduced pressure untilamide Y-136 precipitates as a fine orange powder that is shortlytriturated with MeOH, filtered and dried under high vacuum (0.73 g).

Physical characteristics are as follows:

¹H-NMR (d₆-DMSO, 300 MHz) δ8.87, 8.62, 8.04, 7.81, 7.22, 4.54, 2.77,2.67, 1.38.

¹³C-NMR (d₆-DMSO, 75 MHz) δ169.80, 169.02, 164.80, 162.45, 159.55,144.98, 140.43, 131.93, 128.22, 126.74, 123.52, 113.30, 112.28, 81.05,80.44, 53.60, 37.24, 27.60, 27.48.

MS (EI) m/z 515 (M⁺), 459, 358, 172, 116, 57.

HRMS (EI) 535.1826.

Karl-Fischer titration: 2.80% (0.82 eq.)

Anal. Found: C, 53.75; H, 5.71; N, 13.23.

EXAMPLE 262N-{2-[(8-Hydroxyquinolin-7-yl)amido]-1,3,4-thiadiazol-5-yl)-2-benzo-1,3-dioxol-5-ylglycinemonohydrotrifluoroacetate (Z-137) (Refer to Chart Z.)

According to GP VI starting fromN-[5-({1,3-benzodioxol-5-yl-[(tert-butoxy)-carbonyl]methyl}amino)-1,3,4-thiadiazol-2-yl]-8-hydroxy-7-quinolinecarboxamidesemihydrate Y-126 (72 mg) and TFA (10 mL). Acid Z-137 is obtained as ayellow powder (68 mg).

Physical characteristics are as follows:

mp: 220-230° C. (dec).

¹H-NMR (d₆-DMSO, 300 MHz) δ8.90, 8.67, 8.22, 8.07, 7.84, 7.29, 7.00,6.93, 6.01, 5.24.

¹³C-NMR (d₆-DMSO, 75 MHz) δ: 172.39, 166.26, 162.22, 159.24, 154.22,147.86, 147.64, 145.37, 141.93, 136.35, 132.47, 131.10, 128.93, 124.17,121.66, 114.40, 113.39, 108.78, 108.33, 101.69, 60.44.

MS (FAB) m/z 466 (MH⁺), 288, 123.

HRMS (FAB) 466.0826.

EXAMPLE 263N-{2-[(8-Hydroxyquinolin-7-yl)amido]-1,3,4-thiadiazol-5-yl}-2-benzo-1,3-dioxol-4-ylglycinemonohydrotrifluoroacetate (Z-138) (Refer to Chart Z.)

According to GP VI starting fromN-[5-({1,3-benzodioxol-4-yl-[(tert-butoxy)-carbonyl]methyl}amino)-1,3,4-thiadiazol-2-yl]-8-hydroxy-7-quinolinecarboxamidesemihydrate Y-127 (80 mg) and TFA (10 mL). Acid Z-138 is obtained as ayellow powder (50 mg).

Physical characteristics are as follows:

¹H-NMR (d₆-DMSO, 300 MHz) δ8.90, 8.68, 8.26, 8.06, 7.83, 7.28, 6.86,6.06, 6.05, 5.47.

¹³C-NMR (d₆-DMSO, 75 MHz) δ171.57, 166.24, 162.30, 159.21, 154.30,147.67, 145.82, 145.32, 142.04, 136.25, 132.47, 128.97, 124.18, 122.33,120.69, 118.81, 114.44, 113.37, 108.90, 101.62, 54.87.

MS (FAB) m/z 466 (MH⁺), 542, 420.

HRMS (FAB) 466.0830.

EXAMPLE 264N-{2-[(8-Hydroxyquinolin-7-yl)amido]-1,3,4-thiadiazol-5-yl}-tryptophanmonohydrotrifluoroacetate (Z-139) (Refer to Chart Z.)

According to GP VI starting from(S)—N-[5-({1-[(tert-butoxy)carbonyl]-2-indol-3-ylethyl}amino)-1,3,4-thidiazol-2-yl]-8-hydroxy-7-quinolinecarboxamidemonohydrate Y-134 (253 mg) and TFA (15 mL). Acid Z-139 is obtained as ayellow powder (270 mg).

Physical characteristics are as follows:

¹H-NMR (d₆-DMSO, 300 MHz) δ8.91, 8.72, 8.15, 8.08, 7.77, 8.55, 7.30,7.16, 7.02, 6.95, 4.54, 3.32, 3.14.

¹³C-NMR (d₆-DMSO, 75 MHz) δ173.29, 166.82, 162.67, 158.91, 154.52,145.04, 143.04, 136.54, 135.27, 132.54, 129.13, 127.67, 124.48, 124.27,121.44, 118.93, 118.69, 114.69, 113.54, 111.89, 109.63, 57.98.

MS (FAB) m/z 475 (MH⁺), 551, 529, 305, 172.

HRMS (FAB) 475.1198.

Following procedures analogous to those described above, the additionalcompounds of the present invention of Tables 13 and 14 are prepared.

TABLE 1 Compound of CMV pol Assay Example No. Conc (M) pol type % InhibIC50 uM 1 CMV 10.2 3.13E − 06 CMV −1.5 6.25E − 06 CMV 22.8 1.30E − 05CMV 66.2 2.50E − 05 CMV 94.7 5.00E − 05 CMV 98.6 1.00E − 04 CMV 100 2CMV 4.3 3.13E − 06 CMV 43.6 6.25E − 06 CMV 59.2 1.30E − 05 CMV 65.72.50E − 05 CMV 78 5.00E − 05 CMV 81.9 1.00E − 04 CMV 83 3 CMV 7.1 3.13E− 06 CMV 20.5 6.25E − 06 CMV 36.5 1.30E − 05 CMV 75.7 2.50E − 05 CMV97.8 5.00E − 05 CMV 100.1 1.00E − 04 CMV 100.2 4 CMV 3.9 3.13E − 06 CMV48.4 6.25E − 06 CMV 48 1.30E − 05 CMV 61.1 2.50E − 05 CMV 59.3 5.00E −05 CMV 47.6 1.00E − 04 CMV 51.9 CMV 3.1 3.13E − 07 CMV 7.2 6.25E − 07CMV 15.1 1.25E − 06 CMV 22.6 2.50E − 06 CMV 50.4 5.00E − 06 CMV 65.41.00E − 05 CMV 75.1 CMV 5.1 7.81E − 07 CMV 4.1 1.56E − 06 CMV 20.6 3.13E− 06 CMV 42.8 6.25E − 06 CMV 58.1 1.30E − 05 CMV 69.7 2.50E − 05 CMV85.6 5 CMV 6.8 3.13E − 06 CMV 29.1 6.25E − 06 CMV 44 1.30E − 05 CMV 69.32.50E − 05 CMV 87.2 5.00E − 05 CMV 95.9 1.00E − 04 CMV 98.7 6 CMV 4.13.13E − 06 CMV 39.6 6.25E − 06 CMV 59 1.30E − 05 CMV 81.1 2.50E − 05 CMV95.1 5.00E − 05 CMV 98.6 1.00E − 04 CMV 99.6 7 CMV 6.9 3.13E − 06 CMV29.6 6.25E − 06 CMV 47.2 1.30E − 05 CMV 64.2 2.50E − 05 CMV 83.1 5.00E −05 CMV 90.6 1.00E − 04 CMV 94.7 8 CMV 20.1 3.13E − 06 CMV 19.3 6.25E −06 CMV 33.4 1.30E − 05 CMV 38.1 2.50E − 05 CMV 52 5.00E − 05 CMV 59.61.00E − 04 CMV 71 9 CMV 2.5 3.13E − 06 CMV 45.6 6.25E − 06 CMV 80.31.30E − 05 CMV 93.3 2.50E − 05 CMV 96.3 5.00E − 05 CMV 99.2 1.00E − 04CMV 98.8 10 CMV 19 3.13E − 06 CMV −8.6 6.25E − 06 CMV 0.8 1.30E − 05 CMV28.4 2.50E − 05 CMV 77.7 5.00E − 05 CMV 95.8 1.00E − 04 CMV 98.6 11 CMV1.3 3.13E − 06 CMV 66 6.25E − 06 CMV 90.5 1.30E − 05 CMV 95.1 2.50E − 05CMV 98.2 5.00E − 05 CMV 97.9 1.00E − 04 CMV 98.3 12 CMV 15.9 3.13E − 06CMV −2.5 6.25E − 06 CMV 3.8 1.30E − 05 CMV 38.6 2.50E − 05 CMV 85 5.00E− 05 CMV 99.4 1.00E − 04 CMV 99.3 13 CMV >100 3.13E − 006 CMV −12.56.25E − 006 CMV 15.4 1.30E − 005 CMV 18.8 2.50E − 005 CMV 26.3 5.00E −005 CMV 17.3 1.00E − 004 CMV 33.8 14 CMV 23.4 3.13E − 06 CMV −4.4 6.25E− 06 CMV 5.5 1.30E − 05 CMV 42.4 2.50E − 05 CMV 59.3 5.00E − 05 CMV 69.91.00E − 04 CMV 84.5 15 CMV 1.6 3.13E − 07 CMV 12.9 6.25E − 07 CMV 19.71.25E − 06 CMV 43 2.50E − 06 CMV 70.2 5.00E − 06 CMV 87.1 1.00E − 05 CMV93.4 16 CMV 5.8 3.13E − 06 CMV 18.2 6.25E − 06 CMV 46.3 1.30E − 05 CMV87.7 2.50E − 05 CMV 96.6 5.00E − 05 CMV 95.6 1.00E − 04 CMV 90.4

TABLE 2 Example No. Conc (M) pol type % Inhib IC50 uM 17 CMV 11.3 3.13e− 006 CMV 0.7 6.25e − 006 CMV 26.4 1.30e − 005 CMV 57.1 2.50e − 005 CMV89 5.00e − 005 CMV 95.5 1.00e − 004 CMV 97.5 18 CMV 27.9 3.13e − 006 CMV5.3 6.25e − 006 CMV 14.9 1.30e − 005 CMV 13.9 2.50e − 005 CMV 51.7 5.00e− 005 CMV 79.6 1.00e − 004 CMV 91.8 19 3.13e − 006 CMV 11.8 6.25e − 006CMV 20 1.30e − 005 CMV 28.9 2.50e − 005 CMV 56.6 5.00e − 005 CMV 69.11.00e − 004 CMV 83.9 CMV 23.6 20 CMV 14.5 3.13e − 006 CMV 10.9 6.25e −006 CMV 25.5 1.30e − 005 CMV 41.3 2.50e − 005 CMV 73.2 5.00e − 005 CMV92 1.00e − 004 CMV 95.4 21 CMV 7.5 3.13e − 006 CMV 33.5 6.25e − 006 CMV43.4 1.30e − 005 CMV 57.2 2.50e − 005 CMV 85.2 5.00e − 005 CMV 94.41.00e − 004 CMV 96.6 22 CMV 12.6 3.13e − 006 CMV 17.6 6.25e − 006 CMV35.3 1.30e − 005 CMV 45.1 2.50e − 005 CMV 69.9 5.00e − 005 CMV 90.81.00e − 004 CMV 97.9 22 CMV 8.6 3.13e − 006 CMV 13.2 6.25e − 006 CMV33.3 1.30e − 005 CMV 68.9 2.50e − 005 CMV 90.7 5.00e − 005 CMV 96.71.00e − 004 CMV 98.2 CMV 4.5 3.13e − 006 CMV 43.3 6.25e − 006 CMV 51.51.30e − 005 CMV 78.3 2.50e − 005 CMV 95.2 5.00e − 005 CMV 98.6 1.00e −004 CMV 99.7 23 CMV 2 3.13e − 006 CMV 48 6.25e − 006 CMV 90.9 1.30e −005 CMV 98.8 2.50e − 005 CMV 99.4 5.00e − 005 CMV 99.4 1.00e − 004 CMV98.3 CMV 3.1 3.13e − 007 CMV 16.3 6.25e − 007 CMV 13 1.25e − 006 CMV14.7 2.50e − 006 CMV 34.6 5.00e − 006 CMV 83.9 1.00e − 005 CMV 99.9 24CMV >100 3.13e − 006 CMV 7.9 6.25e − 006 CMV 8 1.30e − 005 CMV 9.9 2.50e− 005 CMV 3.9 5.00e − 005 CMV −6.4 1.00e − 004 CMV −0.3 CMV 4.5 3.13e −006 CMV 36.5 6.25e − 006 CMV 55.4 1.30e − 005 CMV 82.4 2.50e − 005 CMV97.5 5.00e − 005 CMV 99.3 1.00e − 004 CMV 98.8 25 3.13e − 006 CMV 48.76.25e − 006 CMV 63.3 1.30e − 005 CMV 69.4 2.50e − 005 CMV 76.6 5.00e −005 CMV 83.7 1.00e − 004 CMV 87.6 CMV 3.6 26 CMV 4.6 3.13e − 006 CMV32.1 6.25e − 006 CMV 60.2 1.30e − 005 CMV 79.5 2.50e − 005 CMV 86.45.00e − 005 CMV 87.8 1.00e − 004 CMV 90.1 27 CMV 14.8 3.13e − 006 CMV27.2 6.25e − 006 CMV 36.6 1.30e − 005 CMV 33.5 2.50e − 005 CMV 58.75.00e − 005 CMV 93.5 1.00e − 004 CMV 96.7 28 CMV 5.5 3.13e − 006 CMV28.1 6.25e − 006 CMV 52 1.30e − 005 CMV 78.3 2.50e − 005 CMV 93 5.00e −005 CMV 94.6 1.00e − 004 CMV 96.4 29 CMV 18.3 3.13e − 006 CMV 40.9 6.25e− 006 CMV 33.9 1.30e − 005 CMV 36.1 2.50e − 005 CMV 44.4 5.00e − 005 CMV54.1 1.00e − 004 CMV 71.4 CMV 40.1 3.13e − 006 CMV 27.3 6.25e − 006 CMV27.3 1.30e − 005 CMV 32.9 2.50e − 005 CMV 42 5.00e − 005 CMV 45.8 1.00e− 004 CMV 64 30 CMV 4.3 3.13e − 006 CMV 42.6 6.25e − 006 CMV 59.9 1.30e− 005 CMV 73.4 2.50e − 005 CMV 87.5 5.00e − 005 CMV 95.4 1.00e − 004 CMV97 31 CMV <3.1 3.13e − 006 CMV 82.9 6.25e − 006 CMV 95 1.30e − 005 CMV97.3 2.50e − 005 CMV 97.8 5.00e − 005 CMV 97.8 1.00e − 004 CMV 97.3 CMV3.7 3.13e − 007 CMV −7.9 6.25e − 007 CMV 20 1.25e − 006 CMV 22.7 2.50e −006 CMV 38.5 5.00e − 006 CMV 55 1.00e − 005 CMV 88.2 32 CMV <3.1 3.13e −006 CMV 75.1 6.25e − 006 CMV 89.1 1.30e − 005 CMV 94.6 2.50e − 005 CMV96.3 5.00e − 005 CMV 97.5 1.00e − 004 CMV 98.2 CMV 4.7 3.13e − 007 CMV−14.4 6.25e − 007 CMV 9.8 1.25e − 006 CMV 20.6 2.50e − 006 CMV 30.45.00e − 006 CMV 47.9 1.00e − 005 CMV 85.2 33 CMV 12.8 3.13e − 006 CMV−10.5 6.25e − 006 CMV 38.7 1.30e − 005 CMV 45.7 2.50e − 005 CMV 78 5.00e− 005 CMV 87.9 1.00e − 004 CMV 95.4

TABLE 3 Example No. Concentration (uM) % Inhibition IC₅₀ (uM) 34 100 9717.2 50 54 25 63 12.5 57 6.25 21 35 100 96 10.0 50 89 12.5 44 6.25 413.13 31 36 200 19 >200 100 3 50 15 25 0 12.5 6 6.25 −3 3.13 −1 37 100 5572.3 50 50 25 21 12.5 12 6.25 3 38 100 97 10.5 50 96 25 62 12.5 58 6.2536 39 200 90 21.6 100 71 50 79 25 41 12.5 43 6.25 28 3.13 16 40 100 9413.7 50 80 25 53 12.5 47 6.25 36 3.13 22

TABLE 4 % Inh - IC50 Example No. Conc (uM) AV (AV) 41 2.00e + 000 56.01.00e + 001 92.0 0.5 5.00e + 001 78.0 4.00e + 001 76.0 2.00e + 001 76.01.4 4.00e + 000 70.0 8.00e − 001 39.0 4.00e + 001 99.0 3.8 2.00e + 00186.0 3.8 8.00e + 000 78.0 3.8 4.00e + 000 65.0 3.8 8.00e − 001 0.0 3.842 8.00e − 001 0.0 5.2 4.00e + 000 51.0 5.2 2.00e + 001 88.0 5.2 4.00e +001 92.0 5.2 4.00e + 001 99.0 <0.1 2.00e + 001 99.0 <0.1 4.00e + 00089.0 <0.1 43 8.00e − 001 65.0 0.12 4.00e + 000 77.0 0.12 2.00e + 00190.0 0.12 4.00e + 001 85.0 0.12 4.00e + 001 81.0 0.44 4.00e + 000 88.00.44 8.00e − 001 43.0 0.44 4.00e − 001 50.0 0.44 2.00e + 001 <0.51.00e + 001 99.0 <0.5 5.00e + 000 99.0 <0.5 2.50e + 000 99.0 <0.51.25e + 000 87.0 <0.5 44 8.00e − 001 23.0 2.7 4.00e + 000 65.0 2.72.00e + 001 88.0 2.7 4.00e + 001 93.0 2.7 4.00e + 001 44.0 2.00e + 00143.0 4.00e + 000 59.0 8.00e − 001 58.0 45 8.00e − 001 39.0 1.2 4.00e +000 75.0 1.2 2.00e + 001 83.0 1.2 4.00e + 001 89.0 1.2

TABLE 5 Example No. Conc (M) pol type % Inhib IC50 uM 46 5.00e − 005 CMV67.1 1.00e − 004 CMV 83.2 2.50e − 005 CMV 54.2 CMV 23.3 3.13e − 006 CMV13.9 6.25e − 006 CMV 23 1.30e − 005 CMV 30.7 47 3.13e − 006 CMV 76.56.25e − 006 CMV 61.3 1.30e − 005 CMV 54.3 2.50e − 005 CMV 59.4 5.00e −005 CMV 65.9 1.00e − 004 CMV 73.1 CMV 0.35 7.81e − 008 CMV 5.6 1.56e −007 CMV 20.3 3.13e − 007 CMV 48.6 6.25e − 007 CMV 76.7 1.25e − 006 CMV88.5 2.50e − 006 CMV 94.9 1.25e − 006 CMV 96.4 2.50e − 006 CMV 96.75.00e − 006 CMV 96.1 1.00e − 005 CMV 95.5 6.25e − 007 CMV 93.2 CMV <0.33.13e − 007 CMV 80.5 48 CMV 0.5 3.13e − 007 CMV 32.6 6.25e − 007 CMV61.3 1.25e − 006 CMV 77.2 2.50e − 006 CMV 87.2 5.00e − 006 CMV 91.81.00e − 005 CMV 95.6 3.13e − 006 CMV 97.2 6.25e − 006 CMV 96.8 1.30e −005 CMV 97.5 2.50e − 005 CMV 97.8 5.00e − 005 CMV 98.8 1.00e − 004 CMV97.8 CMV <3.1 49 3.13e − 006 CMV 95.2 6.25e − 006 CMV 96 1.30e − 005 CMV97 2.50e − 005 CMV 97.3 5.00e − 005 CMV 97.2 1.00e − 004 CMV 98.4 CMV<3.1 CMV 0.6 3.13e − 007 CMV 41.2 6.25e − 007 CMV 49.3 1.25e − 006 CMV66.8 2.50e − 006 CMV 85.5 5.00e − 006 CMV 92.8 1.00e − 005 CMV 96.1 505.00e − 005 CMV 92.6 1.00e − 004 CMV 95.6 2.50e − 005 CMV 80.9 CMV <3.13.13e − 006 CMV 83.7 6.25e − 006 CMV 91.1 1.30e − 005 CMV 92.6 2.50e −005 CMV 96 5.00e − 005 CMV 97.1 1.00e − 004 CMV 97.7 CMV 1.2 3.13e − 006CMV 23.2 6.25e − 006 CMV 34.9 1.30e − 005 CMV 40.1 51 CMV <3.1 3.13e −006 CMV 97.1 6.25e − 006 CMV 96.6 1.30e − 005 CMV 96.8 2.50e − 005 CMV96.9 5.00e − 005 CMV 97.9 1.00e − 004 CMV 98.7 CMV 0.17 3.13e − 006 CMV60.2 6.25e − 006 CMV 86.7 1.30e − 005 CMV 94.2 2.50e − 005 CMV 98.25.00e − 005 CMV 98.7 1.00e − 004 CMV 98.4 52 CMV <3.1 3.13e − 006 CMV97.4 6.25e − 006 CMV 98.4 1.30e − 005 CMV 98.9 2.50e − 005 CMV 98.75.00e − 005 CMV 98.5 1.00e − 004 CMV 98.6 CMV 0.17 3.13e − 006 CMV 59.76.25e − 006 CMV 84.6 1.30e − 005 CMV 95.2 2.50e − 005 CMV 97.3 5.00e −005 CMV 98.7 1.00e − 004 CMV 99 53 CMV <3.1 3.13e − 006 CMV 94.6 6.25e −006 CMV 94.2 1.30e − 005 CMV 94.7 2.50e − 005 CMV 95.8 5.00e − 005 CMV92.7 1.00e − 004 CMV 95.8 CMV 0.3 3.13e − 007 CMV 46 6.25e − 007 CMV68.2 1.25e − 006 CMV 84.8 2.50e − 006 CMV 92.8 5.00e − 006 CMV 95.41.00e − 005 CMV 94.9 54 CMV <3.1 3.13e − 006 CMV 88.7 6.25e − 006 CMV94.4 1.30e − 005 CMV 95.1 2.50e − 005 CMV 95.6 5.00e − 005 CMV 95.6 1.00− e004 CMV 95.3 CMV 0.3 3.13e − 007 CMV 45.9 6.25e − 007 CMV 77.8 1.25e− 006 CMV 89.6 2.50e − 006 CMV 94.2 5.00e − 006 CMV 97.3 1.00e − 005 CMV98.7 55 CMV 31.5 3.13e − 006 CMV 17.2 6.25e − 006 CMV 27.4 1.30e − 005CMV 27.7 2.50e − 005 CMV 42.9 5.00e − 005 CMV 51.4 1.00e − 004 CMV 73.556 CMV 19.7 3.13e − 006 CMV 27.9 6.25e − 006 CMV 30 1.30e − 005 CMV 36.82.50e − 005 CMV 48.4 5.00e − 005 CMV 59.8 1.00e − 004 CMV 81.8 58 3.13e− 006 CMV −2.9 6.25e − 006 CMV 2.4 1.30e − 005 CMV 27.9 2.50e − 005 CMV40.2 5.00e − 005 CMV 46.2 1.00e − 004 CMV 65 3.13e − 006 CMV −2.9 6.25e− 006 CMV 2.4 1.30e − 005 CMV 27.9 2.50e − 005 CMV 40.2 5.00e − 005 CMV46.2 1.00e − 004 CMV 65 3.13 − 006 CMV −2.9 6.25 − 006 CMV 2.4 1.30e −005 CMV 27.9 2.50e − 005 CMV 40.2 5.00e − 005 CMV 46.2 1.00e − 004 CMV65 CMV 49.7 3.13e − 006 CMV −2.9 6.25e − 006 CMV 2.4 1.30e − 005 CMV27.9 2.50e − 005 CMV 40.2 5.00 − 005 CMV 46.2 1.00e − 004 CMV 65 57 CMV8.0

TABLE 6 Concentration Example No. (μM) % Inhibition IC₅₀ (μM) Example 59200 43 >200 100 31 50 14 25 0 12.5 −3 6.25 −6 3.13 −7 Example 60 200 7057.4 100 55 50 51 25 32 12.5 31 6.25 19 3.13 30 Example 61 200 51 >200100 38 50 30 25 30 12.5 23 6.25 15 3.13 13 Example 62 200 42 >200 100 3350 14 25 10 12.5 6 6.25 3 3.13 1 Example 63 100 92 11.4 50 74 25 71 12.549 6.25 34 3.13 29 Example 64 200 84 29.8 100 58 50 75 25 46 12.5 256.25 25 3.13 16 Example 65 200 −8 >200 100 −23 50 −23 25 −21 12.5 −136.25 −8 3.13 −8 Example 66 200 89 11.0 100 86 50 64 25 57 12.5 60 6.2541 3.13 32 200 88 17.9 100 91 50 71 25 77 12.5 37 6.25 30 3.13 13Example 67 200 94 23.6 100 86 50 76 25 41 12.5 25 6.25 23 3.13 13

TABLE 7 Antiviral Selective Polymerase IC50 Values - Example Number,Structure Polymerase IC50 (uM)

CMV 9.7 9.4

CMV 42.8

CMV <3.1

CMV 13.3 CMV Antiviral Assay % Inh - IC50 Example Number, Structure Conc(uM) AV (AV)

2.00e+001 4.00e+000 8.00e−001 90.0 41.0 34.0 3 3 3

4.00e+001 2.00e+001 4.00e+000 8.00e+001 4.00e+001 3.00e+001 2.00e+0011.00e+001 8.00e+000 4.00e+000 99.0 96.0 12.0 21.0 66.0 52.0 54.0 50.035.0 8.0 3 3 3 3 14.1 14.1 14.1 14.1 14.1 14.1

TABLE 8 MS- MS- Com- ESI ESI pound (+) (−) NMR (d) (CDCl3) Elem. Anal.75 332 330 8.8, 8.2, 8.1, 7.9, 7.5, 7.4, 7.3, 7.2, 7.1, 3.9, 3.2 76 309307 77 385 383 78 347 345 79 347 345 80 329 327 81 321 319 82 301 2998.8, 8.2, 7.8, 7.5, 7.4, 3.5, 1.7, 1.5-1.2, 0.9 83 347 345 84 347 345 85297 295 86 361 359 8.8, 8.2, 7.9, 7.5, 7.4, 7.2, 3.8, 3.1 87 325 323 88313 311 89 293 291 90 293 291 91 313 311 92 309 307 8.8, 8.3, 8.2, 7.6,7.5, 7.4, 5.0, 4.0, 3.7 93 369 367 94 308 306 95 301 299 8.8, 8.2, 7.8,7.5, 7.4, 3.5, 1.6, 1.5-1.2, 1.0, 0.9 96 343 341 97 441 439 98 371 36999 327 325 100 307 305 101 383 381 102 307 305 103 315 313 8.8, 8.2,7.8, 7.5, 7.4, 3.5, 1.7, 1.5-1.2, 0.9 104 315 313 105 313 311 106 285283 107 299 297 108 285 283 109 285 283 110 319 317 111 299 297 112 305303 113 285 283 114 355 353 115 293 291 116 287 282 117 301 299 118 327325 119 409 407 120 343 341 121 343 341 122 293 291 123 373 371 124 373371 125 385 383 126 385 383 127 283 281 128 325 323 129 339 337 130 367365 8.8, 8.2, 8.1, 7.5, 7.4-7.2, 5.3, 5.0, 4.2 131 367 355 8.8, 8.2,8.1, 7.5, 7.4, 7.1, 6.8, 5.1, 3.8, 3.2 132 404 402 133 323 321 134 457455 135 396 394 136 315 313 137 287 285 138 331 329 139 347 345 140 347345 141 391 389 142 407 405 143 405 403 144 417 415 145 444 442 146 285283 8.8, 8.2, 7.9, 7.5, 7.4, C 71.57, H 7.08, N 9.87 3.4, 1.9-1.6,1.4-1.0 147 329 327 8.8, 8.2, 7.8, 7.6-7.4, C 76.52, H 5.19, N 8.59 7.3,5.2 148 327 325 10.0, 8.8, 8.2, 8.0, 7.5, C 65.82, H 4.63, N 8.56 7.3,7.2, 7.1, 3.8, 3.0 149 347 345 9.6, 8.8, 8.4, 8.2, C 66.22, H 4.09, N8.04 7.7-7.3, 4.8 150 325 323 10.0, 8.8, 8.2, 8.1, 7.5, C 66.48, H 5.06,N 8.55 7.4, 7.3, 7.2, 7.1, 3.8, 3.2 151 287 285 10, 8.8, 8.1, 7.8, 7.5,7.3, 3.5, 1.7, 1.5-1.2, 0.9

TABLE 9 CMV pol Assay - Example Number, Structure IC50 uM

0.9

<1.5

1.5

<3.1 1.6 20

1.7

2.2 4.7

2.2

2.3

<3.1 2.4 10.8

2.6

2.9 6.4

3

3.1

<3.1

<3.1 >10

3.1

3.2

3.7

4.5

4.6

4.9

5

5.2

5.2

5.6

5.6

6.6

6.7

6.9

7.1

7.1

7.4

7.6

7.6

7.8

7.9

8.1

8.1

8.4

8.4

8.5

8.7

9

11.3 9.2

9.2

9.3

9.4

9.6

10.8

11.1

12.1

12.6

13.2

13.7

14.6

14.8

15.7

16.8

17

17.5

19.2

19.3

19.7

20.1

20.6

20.7

21.1

22.2

22.3

22.6

23.2

23.3

23.8

24.2

24.3

24.5

24.6 29.4

TABLE 10 CMV pol Assay Example Number, Structure Conc (M) pol type %Inhib IC50 uM

1.00e−004 5.00e−005   3.13e−006 6.25e−006 1.30e−005 2.50e−005 1.00e−004CMV CMV CMV CMV CMV CMV CMV CMV 98.7 87.6   2.5 3.4 11.8 43.1 98.2    30.1

  3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005 1.00e−004 1.00e−004CMV CMV CMV CMV CMV CMV CMV CMV   7 6.2 12.8 23.1 28.5 44 99.9 >100

  3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005 1.00e−004 1.00e−004CMV CMV CMV CMV CMV CMV CMV CMV   56.8 90.6 99.7 99.8 100.8 100.3 99.91.7

  3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005 1.00e−004 1.00e−004CMV CMV CMV CMV CMV CMV CMV CMV   2.6 9.8 13.6 28.9 40.7 60 63.8 68.2

  3.13e−007 6.25e−007 1.25e−006 2.50e−006 5.00e−006 1.00e−005  3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005 1.00e−004 CMV CMV CMVCMV CMV CMV CMV CMV CMV CMV CMV CMV CMV CMV   13.8 32.1 40.9 57.8 65.374.6   78.1 79.8 82.9 83.6 82.8 90.8 1.8             <3.1

  3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005 1.00e−004 CMV CMVCMV CMV CMV CMV CMV   −3.9 3.3 6.6 15.8 20.5 57.2 90

  3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005 1.00e−004 CMV CMVCMV CMV CMV CMV CMV   −4.2 11.9 39.1 75.6 98.2 100 16.4

  3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005 1.00e−004 CMV CMVCMV CMV CMV CMV CMV   26.8 44.1 55.4 63.4 76.3 86.2 9.5

  3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005 1.00e−004 1.00e−004CMV CMV CMV CMV CMV CMV CMV CMV   3.1 4.8 30 82.9 100 100.3 98.7 16.9

  3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005 1.00e−004 CMV CMVCMV CMV CMV CMV CMV   0.4 7.1 8.4 26.2 26.5 59 82.9

  3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005 1.00e−004 CMV CMVCMV CMV CMV CMV CMV   1.1 6.6 32.7 58.1 68.8 80.6 26.3

1.25e−007 6.25e−006 1.30e−005 2.50e−005 5.00e−005 1.00e−004 CMV CMV CMVCMV CMV CMV CMV −0.2 10.4 18.3 34.6 50.3 71.3             48.4

1.00e−004   3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005 CMV CMVCMV CMV CMV CMV CMV 93.2   12 24.4 45.5 74.3 88.1   14

  3.13e−006 3.13e−006 6.25e−006 6.25e−006 1.30e−005 1.30e−005 2.50e−0052.50e−005 5.00e−005 5.00e−005 1.00e−004 1.00e−004 CMV CMV CMV CMV CMVCMV CMV CMV CMV CMV CMV CMV CMV   7.8 29.7 11.2 47.1 9.4 88.8 19.5 102.448.8 103 91.1 102.7 14.7

  3.13e−006 3.13e−006 6.25e−006 6.25e−006 1.30e−005 1.30e−005 2.50e−0052.50e−005 5.00e−005 5.00e−005 1.00e−004 1.00e−004 CMV CMV CMV CMV CMVCMV CMV CMV CMV CMV CMV CMV CMV   6 26.3 2.3 35.6 5.8 69.7 9.5 101.818.1 103.6 65.8 102.8 22.4

  3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005 1.00e−004 CMV CMVCMV CMV CMV CMV CMV   17 18.6 41.9 91.9 102.8 102.9 12.2

2.50e−005   3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005 1.00e−004CMV CMV CMV CMV CMV CMV CMV 73.7   13.2 21.2 29,7 77.9 98.6 100   15.5

2.50e−005   1.56e−006 3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005CMV CMV CMV CMV CMV CMV CMV CMV 90.8   26 58.1 87.3 97.6 99 99.4   2.4

2.50e−005   1.56e−006 3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005CMV CMV CMV CMV CMV CMV CMV CMV 90.6   10 15.6 26.7 68.5 96.3 99.8   9.2

2.50e−005   3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005 1.00e−004CMV CMV CMV CMV CMV CMV CMV CMV 71.5   9.8 15.5 19.9 59.5 69.9 51.4  32.7

2.50e=005 CMV 30.6

5.00e−005 2.50e−005 2.50e−005   1.56e−006 3.13e−006 6.25e−006 1.30e−005CMV CMV CMV CMV CMV CMV CMV CMV 99.6 98 95.4   13.9 23 47.4 87.7      5.9

2.50e−005   1.56e−006 3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005CMV CMV CMV CMV CMV CMV CMV CMV 85.3   17.4 49.8 85.1 97.2 98.3 99.1  2.9

2.50e−005   1.56e−006 3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005CMV CMV CMV CMV CMV CMV CMV CMV 91.9   7.7 15.2 11.9 19.5 57.3 91.1  25.5

6.25e−006 1.30e−005 2.50e−005 5.00e−005 3.13e−006 2.50e−005   1.56e−006CMV CMV CMV CMV CMV CMV CMV CMV 13.1 23.1 75.4 99.1 11.1 84   5.9            19.2

2.50e−005   3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005 1.00e−004CMV CMV CMV CMV CMV CMV CMV CMV 79.6   10.7 16 14.4 37.1 85.3 99.7  29.7

1.00e−004 5.00e−005 2.50e−005   3.13e−006 6.25e−006 1.30e−005 2.50e−005CMV CMV CMV CMV CMV CMV CMV CMV 99.2 98.3 68   17.2 39.8 78.5 95.3      6.9

2.50e−005   3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005 1.00e−004CMV CMV CMV CMV CMV CMV CMV CMV 67.1   8.9 15.2 19.5 38.9 77.2 98.8  30.5

2.50e−005 CMV 37.8

  3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005 1.00e−004 2.50e−005CMV CMV CMV CMV CMV CMV CMV CMV   24.7 26.3 30.5 43 41.3 52.7 41.8 >100

  3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005 1.00e−004 2.50e−005CMV CMV CMV CMV CMV CMV CMV CMV   30.8 63 88.9 97 97.8 98 42.7 4.1

2.50e−005 5.00e−005 1.00e−004   3.13e−006 6.25e−006 1.30e−005 2.50e−005CMV CMV CMV CMV CMV CMV CMV CMV 87.3 77.3 71.8   31.3 65.7 82.9 37.5      3.9

2.50e−005 CMV 37.6

2.50e−005   1.56e−006 3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005CMV CMV CMV CMV CMV CMV CMV CMV 91.3   23.8 32.2 53 86.3 98.5 99.5   4.9

2.50e−005 CMV 30.5

2.50e−005   1.56e−006 3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005CMV CMV CMV CMV CMV CMV CMV CMV 81.8   −6 −5.4 −0.7 2.7 27.6 83.2   27.9

2.50e−005   1.56e−006 3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005CMV CMV CMV CMV CMV CMV CMV CMV 52   12.3 17 13.3 40.9 91.4 100.9   13.6

2.50e−005 CMV 30.8

2.50e−005 CMV 22.3

2.50e−005   1.56e−006 3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005CMV CMV CMV CMV CMV CMV CMV CMV 76.6   6.2 27.6 32.7 55.9 78.5 85.2  10.3

2.50e−005 CMV 39.3

2.50e−005   1.56e−006 3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005CMV CMV CMV CMV CMV CMV CMV CMV 52.2   10.8 17.6 16.8 33.2 51.1 75.5  22.4

2.50e−005 CMV 33.1

2.50e−005   1.56e−006 3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005CMV CMV CMV CMV CMV CMV CMV CMV 79.2   2.8 31.7 49.6 70.5 81.1 89.7  7.1

2.50e−005 CMV 35.9

2.50e−005   1.56e−006 3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005CMV CMV CMV CMV CMV CMV CMV CMV 46.7   5.4 4 4.1 10 7 45.7   >50

2.50e−005   1.56e−006 3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005CMV CMV CMV CMV CMV CMV CMV CMV 63.3   7.7 14 5.1 37 85.5 100   16

2.50e−005 CMV 35

2.50e−005   1.56e−006 3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005CMV CMV CMV CMV CMV CMV CMV CMV 47.7   7.9 15 19.8 65.4 96.9 100.8  10.1

2.50e−005   1.56e−006 3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005CMV CMV CMV CMV CMV CMV CMV CMV 57.5   7.6 8 10.4 17.8 36.2 95.5   27.3

2.50e−005   1.56e−006 3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005CMV CMV CMV CMV CMV CMV CMV CMV 63.9   12.3 15.9 9 30 72 99.6   18.5

2.50e−005   1.56e−006 3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005CMV CMV CMV CMV CMV CMV CMV CMV 73.9   2.1 13.6 14.3 20.6 35.7 93.9  26.8

2.50e−005   1.56e−006 3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005CMV CMV CMV CMV CMV CMV CMV CMV 61.4   5.3 8.3 7.9 13.4 31.2 98.4   27.4

2.50e−005   1.56e−006 3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005CMV CMV CMV CMV CMV CMV CMV CMV 94.6   26.5 27.1 32 48.7 92.7 99.4   9.4

2.50e−005 CMV 22.4

2.50e−005 CMV 29.3

2.50e−005   1.56e−006 3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005CMV CMV CMV CMV CMV CMV CMV CMV 91.7   30.1 50.5 64.1 80.2 89.5 95.7  3.3

2.50e−005   1.56e−006 3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005  1.56e−006 3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005 CMV CMVCMV CMV CMV CMV CMV CMV CMV CMV CMV CMV CMV CMV CMV 46.9   18.1 44.569.7 55 49.7 52.9   17.8 29.4 38.9 50 47.2 56.5   6.9             18.9

2.50e−005   1.56e−006 3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005CMV CMV CMV CMV CMV CMV CMV CMV 96.6   22.4 26.3 33.1 68.3 99 99.4   7.5

2.50e−005   1.56e−006 3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005CMV CMV CMV CMV CMV CMV CMV CMV 88.9   23.4 24.4 21.4 46 77.9 98.3  12.5

2.50e−005   1.56e−006 3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005CMV CMV CMV CMV CMV CMV CMV CMV 78.7   −1.3 9.7 3.3 3.7 1.2 −6.5   >100

2.50e−005   1.56e−006 3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005CMV CMV CMV CMV CMV CMV CMV CMV 29.4   24.8 33.6 30.4 35.6 53.8 78.4  13.8

2.50e−005 CMV 91.5

2.50e−005 CMV 37

2.50e−005   1.56e−006 3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005CMV CMV CMV CMV CMV CMV CMV CMV 97.5   23.3 30.1 61.5 92.8 98.4 99.5  4.3

2.50e−005   1.56e−006 3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005CMV CMV CMV CMV CMV CMV CMV CMV 97.5   20.6 23.4 34.2 62.8 95.4 99.7  8.2

2.50e−005 CMV 24

2.50e−005   1.56e−006 3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005CMV CMV CMV CMV CMV CMV CMV CMV 83.8   17.7 20.3 21.9 37.8 84.5 98.7  13.4

2.50e−005   1.56e−006 3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005CMV CMV CMV CMV CMV CMV CMV CMV 88   21.9 30.4 44.9 85.5 99.3 99.3   5.5

2.50e−005   1.56e−006 3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005CMV CMV CMV CMV CMV CMV CMV CMV 96.9   28.8 27.3 31.9 54.6 94.7 99.4  8.6

2.50e−005   1.56e−006 3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005CMV CMV CMV CMV CMV CMV CMV CMV 97.6   19 20.7 32.4 67.9 98.9 99.8   8.1

2.50e−005 CMV 82.2

2.50e−005   1.56e−006 3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005CMV CMV CMV CMV CMV CMV CMV CMV 97.5   11.6 22.1 37.7 76.3 98.4 99.7  7.3

2.50e−005   1.56e−006 3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005CMV CMV CMV CMV CMV CMV CMV CMV 73.5   7.4 23.7 36.9 89.6 100.3 100.7  6.6

2.50e−005   1.56e−006 3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005CMV CMV CMV CMV CMV CMV CMV CMV 69.2   12.2 18.9 28.5 73.9 96.5 100  18.4

2.50e−005   1.56e−006 3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005CMV CMV CMV CMV CMV CMV CMV CMV 97   29.6 31.2 35.6 64.3 98.1 99.6   7

2.50e−005   1.56e−006 3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005CMV CMV CMV CMV CMV CMV CMV CMV 94.2   22.7 26.5 31 46.4 88.6 99.4  10.2

2.50e−005   3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005 1.00e−004CMV CMV CMV CMV CMV CMV CMV CMV 87   36.5 64 93.6 99.3 99.7 99.6   3.6

2.50e−005   3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005 1.00e−004CMV CMV CMV CMV CMV CMV CMV CMV 49   24.4 45 60.8 81.5 92.1 94   7.9

2.50e−005 CMV 39

2.50e−005   3.13e−006 6.25e−005 1.30e−005 2.50e−005 5.00e−005 1.00e−004CMV CMV CMV CMV CMV CMV CMV CMV 95   33.5 77.7 97.6 99.8 99.7 100   3.1

2.50e−005 CMV 24

2.50e−005   3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005 1.00e−004CMV CMV CMV CMV CMV CMV CMV CMV 67   27.4 47.9 66.5 79.4 85.9 87.9   6.9

2.50e−005 CMV 25

2.50e−005 CMV 83

2.50e−005   3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005 1.00e−004CMV CMV CMV CMV CMV CMV CMV CMV 97   23.8 40.8 69.9 95.6 99.5 99.7   7

2.50e−005   3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005 1.00e−004CMV CMV CMV CMV CMV CMV CMV CMV 96   38.2 66 86.1 97.3 99.3 99.6   3.7

2.50e−005 CMV 35

2.50e−005   3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005 1.00e−004  3.13e−007 6.25e−007 1.25e−006 2.50e−006 5.00e−006 1.00e−005 CMV CMVCMV CMV CMV CMV CMV CMV CMV CMV CMV CMV CMV CMV CMV 84   70.9 94.5 9999.2 99.1 99.7   15.5 19.5 19.8 37.9 82.7 99.5   <3.1             2.8

2.50e−005 CMV 29

2.50e−005   3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005 1.00e−004  3.13e−007 6.25e−007 1.25e−006 2.50e−006 5.00e−006 1.00e−005 CMV CMVCMV CMV CMV CMV CMV CMV CMV CMV CMV CMV CMV CMV CMV 94   89.6 98.5 99.699.9 99.4 99.8   14.5 19.7 20.4 62.8 95.2 98.4   <3.1             2

2.50e−005 CMV 23

2.50e−005   1.56e−006 3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005CMV CMV CMV CMV CMV CMV CMV CMV 43.2   18 24.7 28.6 37.5 54.9 58.1  21.6

2.50e−005   1.56e−006 3.13e−006 6.25e−006 1.30e−005 2.50e−005 5.00e−005CMV CMV CMV CMV CMV CMV CMV CMV 82.3   16.8 14.1 16.6 43.6 78.5 96.3  14.5

TABLE 11 CMV pool Assay Example Number, Structure IC50 uM

71

93.2

2.4

2.5

14.3

3.1

15.4

9.4

4.3

4.7

7.1

<3.1

<3.1

11.4

13.9

26.6

<3.1

4.5

24.2

22.6

18.9

8.5

TABLE 12 CMV Antiviral Assay % Inh - IC50 Example Number, Structure Conc(uM) AV (AV)

4.00e+001 2.00e+001 4.00e+000 8.00e+001 33.0 50.0 34.0 28.0 25.5 25.525.5 25.5

4.00e+001 2.00e+001 4.00e+000 8.00e−001 2.00e+001 8.00e+000 4.00e+0001.00e+000 90.0 74.0 66.0 29.0 78.0 12.0 62.0 20.0 2.5 2.5 2.5 2.5 3.63.6 3.6 3.6

4.00e+001 2.00e+001 1.00e+001 4.00e+000 8.00e−001 2.00e+001 1.50e+0011.00e+001 5.00e+000 94.0 69.0 8.0 1.0 4.0 78.0 60.0 45.0 36.0 14.4 14.414.4 14.4 14.4 9.4 9.4 9.4 9.4

2.00e+001 1.00e+001 4.00e+000 8.00e−001 93.0 97.0 54.0 0.0 3.5 3.5 3.53.5

2.00e+001 1.00e+001 4.00e+000 8.00e−001 79.0 26.0 17.0 35.0 14.6 14.614.6 14.6

8.00e+000 4.00e+000 2.00e+000 1.00e+000 63.0 53.0 48.0 0.00 3.9 3.9 3.93.9

TABLE 13 Structure and Name MP (° C.) Mass Spec IC₅₀ (μM)

55-58 (EI) 394, M⁺ 35% inhibition @ 100 uMN-[(4-Chlorophenyl)methyl]-8-hydroxy- 4-methyl-2-(trifluoromethyl)-7-quinolinecarboxamide

163-165 (EI) 312, M⁺ 7.6 N-(4-Chlorophenyl)-8-hydroxy-2-methyl-7-quinolinecarboxamide

218-220 (dec) (EI) 357, M⁺ 2.6 N-[(4-Chlorophenyl)methyl]-8-hydroxy-5-nitro-7-quinolinecarboxamide

289-290 (dec) (EI) 408, M⁺ 5.2 N-[4,5-dihydro-[5-(3-nitrophenyl)]-4-oxo-2-thiazolyl]-8-hydroxy-7- quinolinecarboxamide

249-250 (dec) (EI) 411, M⁺ 1.7 N-[5-[3-(4-Chlorophenyl)methyl]-4,5-dihydro-4-oxo-2-thiazolyl]-8-hydroxy-7- quinolinecarboxamide

127-129 (ESI) 393, M + H 41.6 8-Hydroxy-N-[2-(phenylthio)ethyl]-2-(trifluoromethyl)-7- quinolinecarboxamide

274-276 (ET) 342, M⁺ 102 N-[(4-Chlorophenyl)methyl]-4,8-dihydroxy-2-methyl-7- quinolinecarboxamide

110-111 (ESI) 393, M + H 5.1 (E)-8-Hydroxy-2-(2-phenylethenyl)-N-(3-phenylpropyl)-7-quinolinecarboxamide

TABLE 14 Structure and Name Mass Spec IC50 (μM)

ESI -MS: M + H = 287 ESI-MS: M − H = 285 21% inhibition at 25 uM8-Hydroxy-quinoline-7- carboxylic acid trans-4- hydroxy-cyclohexylamide

ESI -MS M + H = 402 ESI-MS: M − H = 400 14 [4-(3,4-Dichlorophenyl)-piperazin-yl]-(8-hydroxy- quinolin-7-yl)-methanone

ESI -MS: M + H = 323 ESI-MS: M − H = 321 26 8-Hydroxy-quinoline-7-carboxylic acid bezo[1,3]dioxol-5- ylmethylamide

ESI -MS: M + H = 273 ESI-MS: M − H = 271 27 N-Hexyl-8-hydroxy-7-quinolinecarboxamide

ESI -MS: M + H = 354 ESI-MS: M − H = 352 42 8-Hydroxy-quinoline-7-carboxylic acid 2-(5-nitro- pyridin-2-ylamino)- ethylamide

ESI -MS: M + H = 309 ESI-MS: M − H = 307 29 8-Hydroxy-N-[2-(phenyloxy)ethyl]-7- quinolinecarboxamide

ESI -MS: M + H = 323 ESI-MS: M − H = 321 41 8-Hydroxy-quinoline-7-carboxylic acid 2-(R)- hydroxy-1-(S)-methyl-2- phenyl-ethylamide

ESI -MS: M + H = 365 ESI-MS: M − H = 363 41 (S)-2-[(8-Hydroxy-quinoline-7-carbonyl)- amino]-3-phenyl- propionic acid ethyl ester

ESI -MS: M + H = 304 ESI-MS: M − H = 302 54 8-Hydroxy-quinoline-7-carboxylic acid cyano- phenylylamide

ESI -MS: M + H = 359 ESI-MS: M − H = 357 51 (S)-2-[(8-Hydroxy-quinoline-7-carbonyl)- amino]-4-methyl- penatnoic acid tert-butyl

ESI -MS: M + H = 339 ESI-MS: M − H = 337 14 (S,S)-8-Hydroxy-quinoline-7-carboxylic acid 2-hydroxy-1- (hydroxy-phenyl-methyl)-ethylamide

ESI -MS: M + H = 289 ESi-MS: M − H = 287 26 (S,S)-8-Hydroxy-quinoline-7-carboxylic acid 1-hydroxymethyl-2- methyl-butylamide

ESI -MS: M + H = 323 ESI-MS: M − H = 321 93% inhibition at 25 uM(S)-8-Hydroxy-quinoline- 7-carboxylic acid 1- benzyl-2-hydroxy-ethylamide

ESI -MS: M + H = 285 ESI-MS: M − H = 283 34 8-Hydroxy-quinoline-7-carboxylic acid thiophen- 2-ylmethylainide

ESI -MS: M + H = 309 ESI-MS: M − H = 307 19 (R)-8-Hydroxy-quinoline-7-carboxylic acid 2- hydroxy-1-phenyl- ethylamide

ESI -MS: M + H = 327 ESI-MS: M − H = 325 26 N-[2-(2-chlorophenyl)ethyl]-8- hydroxy-7- quinolinecarboxamide

ESI -MS: M + H = 315 ESI-MS: M − H = 313 42 N-[(3,4-Difluorophenyl)methyl]- 8-hydroxy-7- quinolinecarboxamide

ESI -MS: M + H = 331 ESI-MS: M − H = 329 30 N-[(2-Chloro-6-fluoro-phenyl)methyl]-8- hydroxy-7- quinolinecarboxamide

ESI -MS: M + H = 331 ESI-MS: M − H = 329 28 N-[(2-Chloro-4-fluoro-phenyl)methyl]-8 hydroxy-7- quinolinecarboxamide

ESI -MS: M + H = 347 ESI-MS: M − H = 345 27 N-[(3,5-Dichloro-phenyl)methyl]-8- hydroxy-7- quinolinecarboxamide

ESI -MS: M + H = 309 ESI-MS: M − H = 307 39% inhibition at 25 uM(S)-8-Hydroxy-quinoline- 7-carboxylic acid 2- hydroxy-1-phenyl-ethylamide

ESI -MS: M + H = 311 ESI-MS: M − H = 309 39% inhibition at 25 uMN-[2-(2- fluorophenyl)ethyl]-8- hydroxy-7- quinolinecarboxamide

ESI -MS: M + H = 311 ESI-MS: M − H = 309 42% inhibition at 25 uMN-[2-(4- fluorophenyl)ethyl]-8- hydroxy-7- quinolinecarboxamide

ESI -MS: M + H = 458 ESI-MS: M − H = 456 4 trans-8-Hydroxy-quinoline-7-carboxylic acid 4-[(8-hydroxy- quinoline-7-carbonyl)-amino]-cyclohexyl ester

What is claimed is:
 1. A compound formula VI or VII

wherein X is a) C, or b) SO; Y is a) NH, b) O,or c) S; EWG is a) CN, b)COX²—C₁-C₆ alkyl, or c) COOH; X² is a) —O—, or b) —NH; R¹ is a) H, b) F,c) Cl, d) Br, e) CF₃, or f) NO₂; R² is a) H, b) C₁-C₃alkyl, c) OH, d)CF₃, e) CH═CH-furanyl, f) CH═CH-phenyl substituted by zero (0) or one(1) R⁴, g) CH═CH-pyridinyl, h) (CH₂)_(p)-phenyl substituted by zero (0)or one (1) R⁴, i) NHV¹, j) CH₂NHV¹, or k) CH₂Z¹; R³ is a) H, b) OH, c)CF₃, or d) C₁-C₃alkyl; R⁴ is a) H, b) (CH₂)_(n)—CO₂—C₁-C₆ alkyl, c)(CH₂)_(m)-phenyl optionally substituted with one (1) or two (2) R⁷, d)(CH₂)_(m)-het, e) C₁-C₆ alkyl optionally substituted by one R⁶, f) C₁-C₄alkyl-NH—COOCH₂-benzyl, or g) C₁-C₄ alkyl-S—CH₃; R⁵ is pyrrolidin-1-yloptionally substituted with EWG or R⁶; R⁶ is a) hydroxy, b) C₁-C₆alkyloxy, c) mercapto, or d) C₁-C₆ alkylmercapto; R⁷ is a) hydroxy, orb) C₁-C₆ alkyloxy; V¹ is a) R¹¹, b) C(O)R¹¹, c) SO₂R¹¹, or d) C(O)NHR¹¹;Z¹ is a) C₁-C₇ alkyl, b) C₃-C₈ cycloalkyl, c) C(O)R¹¹, d) C(O)NHR¹¹,ore) CO²R¹¹; R¹¹ is a) C₁-C₇ alkyl, b) C₃-C₈ cycloalkyl, c) (CH₂)_(n)X¹,or d) CH₂—C₃-C₈ cycloalkyl; X¹ is a) phenyl substituted by zero (0), one(1), two (2), or three (3) R⁴, b) het substituted by zero (0), one (1)or two (2) R⁵, c) C₁-C₈ alkyl, d) CH(OH)-phenyl, e) S-phenyl, f)NHSO₂-phenyl substituted by one (1), two (2) or three (3) R⁴, g) CN, h)OH, i) C₃-C₈ cycloalkyl, or j) 4-cyano-2,3,5,6-tetrafluoro-phenyl; hetis a 5-, or 6-membered saturated or unsaturated ring containing from one(1) to three (3) heteroatoms selected from the group consisting ofnitrogen, oxygen and sulfur; and including any bicyclic group in whichany of the above heterocyclic rings is fused to a benzene; cycloalkyl isa saturated or unsaturated hydrocarbon ring including any bicyclic groupin which the above ring is connected to a benzene; n is zero (0) tothree (3); m is zero (0) to one (1); and p is one (1), two (2) or three(3).
 2. A compound of claim 1 wherein R⁷ is t-butyl; and het is a)1,3-benzodioxol-4-yl, b) 1,3-benzodioxol-5-yl, or c) indolyl.
 3. Acompound of formula VI-H

wherein X is a) C, or b) SO; Y is a) NH, b) O, or c) S; R¹ is a) H, b)F, c) Cl, d) Br, e) CF₃, or f) NO₂, R² is a) H, b) C₁-C₃alkyl, c) OH, d)CF₃, e) CH═CH-furanyl, f) CH═CH-phenyl substituted by zero (0) or one(1) R⁴, g) CH═CH-pyridinyl, h) (CH₂)_(p)-phenyl substituted by zero (0)or one (1) R⁴, i) NHV¹, j) CH₂NHV¹, or k) CH₂Z¹; R³ is a) H, b) OH, c)CF₃, or d) C₁-C₃alkyl; R⁴ is a) H, b) (CH₂)_(n)—CO₂—C₁-C₆ alkyl, c)(CH₂)_(m)-phenyl optionally substituted with one (1) or two (2) R⁷, d)(CH₂)_(m)-het, e) C₁-C₆ alkyl optionally substituted by one R⁶, f) C₁-C₄alkyl-NH—COOCH₂-benzyl, or g) C₁-C₄ alkyl-S—CH₃; R⁶ is a) hydroxy, b)C₁-C₆ alkyloxy, c) mercapto, or d) C₁-C₆ alkylmercapto; R⁷ is a)hydroxy, or b) C₁-C₆ alkyloxy; V¹ is a) R¹¹, b) C(O)R¹¹, c) SO₂R¹¹, ord) C(O)NHR¹¹; Z¹ is a) C₁-C₇ alkyl, b) C₃-C₈ cycloalkyl, c) C(O)R¹¹, d)C(O)NHR₁₁, or e) CO₂R¹¹; R¹¹ is a) C₁-C₇ alkyl, b) C₃-C₈ cycloalkyl, c)(CH₂)_(n)X¹, or d) CH₂—C₃-C₈ cycloalkyl; X¹ is a) phenyl substituted byzero (0), one (1), two (2), or three (3) R⁴, b) het, c) C₁-C₈ alkyl, d)CH(OH)-phenyl, e) S-phenyl, f) NHSO₂-phenyl substituted by one (1), two(2) or three (3) R⁴, g) CN, h) OH, i) C₃-C₈ cycloalkyl, or j)4-cyano-2,3,5,6-tetrafluoro-phenyl; het is a 5-, or 6-membered saturatedor unsaturated ring containing from one (1) to three (3) heteroatomsselected from the group consisting of nitrogen, oxygen and sulfur; andincluding any bicyclic group in which any of the above heterocyclicrings is fused to a benzene; cycloalkyl is a saturated or unsaturatedhydrocarbon ring including any bicyclic group in which the above ring isconnected to a benzene; n is zero (0) to three (3); m is zero (0) to one(1); and p is one (1), two (2) or three (3).
 4. A compound is selectedfrom the group consisting of:N-[5-({2-[(tert-Butoxy)amido]ethyl}amino)-1,3,4-thiadiazol-2-yl]-8-hydroxy-7-quinolinecarboxamidemonohydrochloride;N-{5-[(1,3-Benzodioxol-5-cyanomethyl)amino]-1,3,4-thiadiazol-2-yl}-8-hydroxy-7-quinolinecarboxamidemonohydrochloride;(S)—N-[5-({Benzyl[(methoxy)carbonyl]methyl}amino)-1,3,4-thiadiazol-2-yl]-8-hydroxy-7-quinolinecarboxamidemonohydrochloride;(R)—N-[5-({Benzyl[(methoxy)carbonyl]methyl}amino)-1,3,4-thiadiazol-2-yl]-8-hydroxy-7-quinolinecarboxamidemonohydrochloride;N-[5-({1,3-Benzodioxol-5-yl-[(tert-butoxy)carbonyl]methyl}amino)-1,3,4-thiadiazol-2-yl]-8-hydroxy-7-quinolinecarboxamidesemihydrate;N-[5-({1,3-Benzodioxol-4-yl-[(tert-butyloxy)carbonyl]methyl}amino)-1,3,4-thiadiazol-2-yl]-8-hydroxy-7-quinolinecarboxamidesemihydrate;N-{5-[(1,3,-Benzodioxol-5-ylmethyl)amino]-1,3,4-thiadiazol-2-yl}-8-hydroxy-7-quinolinecarboxamide;(S)—N-[5-({[(tert-Butoxy)carbonyl]-[4-hydroxybenzyl]methyl}amino)-1,3,4-thiadiazol-2-yl]-8-hydroxy-7-quinolinecarboxamide;(S)—N-[5-({5-[Benzoxy]amido-1-[(tert-butoxy)carbonyl]pentyl}amino)-1,3,4-thiadiazol-2-yl]-8-hydroxy-7-quinolinecarboxamide;(S)—N-[5-({1-[(tert-Butoxy)carbonyl]-3-methylbutyl}amino)-1,3,4-thiadiazol-2-yl]-8-hydroxy-7-quinolinecarboxamidemonohydrate;(S)—N-(5-{2-[(tert-Butoxy)carbonyl]pyrrolidin-N-yl}-1,3,4-thiadiazol-2-yl)-8-hydroxy-7-quinolinecarboxamidesemihydrate;(S)—N-[5-({1-[(tert-Butoxy)carbonyl]-3-[methylmercapto]propyl}amino)-1,3,4-thiadiazol-2-yl]-8-hydroxy-7-quinolinecarboxamidemonohydrate;(S)—N-[5-({1-[(tert-Butoxy)carbonyl]-2-indol-3-ylethyl}amino)-1,3,4-thiadiazol-2-yl]-8-hydroxy-7-quinolinecarboxamidemonohydrate;(S)—N-(5-{1-[(tert-Butoxy)carbonyl]-2-[4-(tert-butoxy)phenyl]ethyl}amino)-1,3,4-thiadiazol-2-yl]-8-hydroxy-7-quinolinecarboxamidemonohydrate;(S)—N-[5-({1,2-Di-[(tert-butoxy)carbonyl]ethyl}amino)-1,3,4-thiadiazol-2-yl]-8-hydroxy-7-quinolinecarboxamidemonohydrate;N-{2-[(8-Hydroxyquinolin-7-yl}amido]-1,3,4-thiadiazol-5-yl}-2-benzo-1,3-dioxol-5-ylglycinemonohydrotrifluoroacetate;N-{2-[(8-Hydroxyquinolin-7-yl)amido]-1,3,4-thiadiazol-5-yl}-2-benzo-1,3-dioxol-4-ylglycinemonohydrotrifluoroacetate; andN-{2-[(8-Hydroxyquinolin-7-yl)amido]-1,3,4-thiadiazol-5-yl}tryptophanmonohydrotrifluoroacetate.
 5. A method for treating a cytomegaloviralinfection in a mammal comprising the administration of a compound ofclaim 1, 3, 4.